Targeting MEK in cancer and beyond: mechanistic insights and therapeutic opportunities.

# Targeting MEK in cancer and beyond: mechanistic insights and therapeutic opportunities *The Lancet 2026* Therapeutics Targeting MEK in cancer and beyond: mechanistic insights and therapeutic opportunities Wei Yen Chan, Ines Pires da Silva, Georgina V Long, Helen Rizos MEK inhibitors are established therapies in BRAF-driven cancers, yet their broader clinical eect is limited by toxicity, Lancet 2026; 407: 1639–56 resistance, and modest durability as a monotherapy, particularly in RAS-mutant tumours. Dose intensity is often Published Online restricted by severe adverse eects, particularly dermatological, gastrointestinal, ocular, and cardiopulmonary toxic April 16, 2026 eects. Predictive biomarkers, such as tumour mutational burden, interferon signatures, and MAPK pathway activity, https://doi.org/10.1016/ S0140-6736(26)00199-6 are emerging as crucial tools for refining patient selection and monitoring therapeutic response. Advances in drug Faculty of Medicine, Health design, including dual-targeting strategies, aim to expand the therapeutic window and overcome resistance and Human Sciences, mechanisms. Combination regimens, particularly those incorporating immune checkpoint inhibitors or PI3K– Macquarie University, Sydney, mTOR pathway inhibition, show promise for enhancing ecacy and treatment durability. Beyond oncology, MEK NSW, Australia (W Y Chan MD, pathway modulation is under investigation in fibrotic, inflammatory, and developmental disorders, although clinical Prof H Rizos PhD); Melanoma validation remains at an early stage. Building on more than a decade of use in BRAFV⁶⁰⁰ (ie, Val600)-mutant melanoma, Institute of Australia, The University of Sydney, Sydney, MEK inhibitors continue to be refined through biomarker-guided combination strategies and exploration in additional NSW, Australia (W Y Chan, cancers and non-oncological diseases. Prof I Pires da Silva PhD, Prof G V Long PhD, Prof H Rizos); Introduction resistance, and adaptive feedback signalling that restores Faculty of Medicine and Health, The University of Sydney, The mitogen-activated protein kinase (MAPK) pathway— MAPK signalling. These challenges have prompted Sydney, NSW, Australia also known as the RAS–RAF–MEK–ERK cascade—is a increasing interest in rational combination strategies (Prof G V Long); Department of Medical Oncology, Royal North highly conserved signalling axis that governs fundamental aimed at augmenting therapeutic response and Shore and Mater Hospitals, processes in cellular and organismal development and circumventing resistance. Strategies under investigation Sydney, NSW, Australia tissue homoeostasis, including organogenesis, include cotargeting parallel oncogenic pathways, (Prof G V Long); Charles Perkins proliferation, survival, and migration.1,2 Dysregulated integrating MEK inhibitors with cytotoxic chemotherapy, Centre, The University of Sydney, Sydney, NSW, Australia MAPK activity is a hallmark of cancer, with activating and combining MEK inhibitors with immune checkpoint (Prof G V Long); Champalimaud mutations in core components such as RAS (eg, KRAS inhibitors.11,12 MEK inhibitors have also been repurposed Foundation, Lisbon, Portugal and NRAS) and BRAF, or loss-of-function mutations in for the treatment of RASopathies, with some notable (Prof I Pires da Silva) negative regulators, such as NF1 (which encodes neurofibromin 1), identified in approximately one-third of all human malignancies (figure 1).3–6 Beyond cancer, Melanoma BRAF germline mutations that aect more than 20 MAPK- NRAS related genes, including PTPN11, SOS1, SOS2, RAF1, KRAS Nerve sheath tumour Thyroid cancer NF1 KRAS, BRAF, MAP2K1 (which encodes MEK1), and NF1, underpin a spectrum of developmental disorders collectively termed RASopathies. These disorders, which 60 include Noonan syndrome, neurofibromatosis type 1, LEOPARD syndrome, and cardiofaciocutaneous syndrome, share phenotypes such as congenital cardiac 20 defects, facial dysmorphism, impaired growth, learning disabilities, and skeletal and ectodermal anomalies.7 Non-small-cell Colorectal cancer lung cancer Given its central role in tumourigenesis and develop- mental disorders, the MAPK cascade has been a major focus of targeted drug development. Signal transduction proceeds through a canonical three-tiered kinase cascade (RAF–MEK–ERK), with MEK1 and MEK2 functioning as the sole activators of the terminal kinases ERK1 and ERK2.8,9 This exclusive positioning renders MEK a Ovarian cancer Pancreatic cancer particularly attractive therapeutic target, and several MEK inhibitors have gained clinical approval. These Endometrial cancer inhibitors are most eective in combination with BRAF inhibitors, eliciting major, occasionally durable, Figure 1: Comparative frequencies of BRAF, KRAS, NRAS, and NF1 alterations across tumour subsets responses in patients with BRAFV⁶⁰⁰ (ie, Val600)-mutant Radar plot showing the frequency of alterations in BRAF, KRAS, NRAS, and NF1 across 95 474 tumour samples from the curated The Cancer Genome Atlas Program dataset. Overall, 24% of tumours harboured alterations in these malignancies, and improving patient survival.10 genes, whereas alterations in MAP2K1 or MAP2K2 were observed in fewer than 2% of cases. Each axis represents The clinical use of MEK inhibition remains constrained one cancer type, with values indicating the frequency of alterations. Data were obtained from cBioPortal and by dose-limiting toxic eects, intrinsic and acquired visualised using Flourish. Therapeutics Correspondence to: improve ments, although long-term safety and optimal The role of MEK in MAPK signalling Prof Helen Rizos, Faculty of dosing remain under investigation.13 The MAPK pathway, anchored by the canonical RAF– Medicine, Health and Human This Therapeutics paper provides a comprehensive MEK–ERK kinase cascade, is initiated by RAS, a small Sciences, Macquarie University, overview of MEK biology, the clinical development of GTPase that cycles between inactive GDP-bound and Sydney, NSW 2109, Australia helen.rizos@mq.edu.au MEK inhibitors, and their therapeutic applications. We active GTP-bound states in response to extracellular discuss key challenges, such as resistance mechanisms, growth factor signalling (figure 2). Upon ligand binding, and explore emerging therapeutic strategies and future receptor tyrosine kinases (RTKs) undergo auto- directions for the clinical application of MEK inhibition phosphorylation and recruit the adaptor proteins GRB2 in cancer therapy. and SOS, which facilitate GDP to GTP exchange on RAS, GRB2 Cytoplasmic substrates Figure 2: Overview of canonical MAPK–ERK signalling cascade and regulatory feedback mechanisms The dotted boxed region denotes the core MAPK module, highlighting the sequential phosphorylation cascade from RAF to MEK to ERK. Activation of receptor tyrosine kinases at the plasma membrane triggers recruitment of adaptor proteins GRB2 and the guanine nucleotide exchange factor SOS, facilitating the conversion of RAS from its inactive GDP-bound form to the active GTP-bound state. Active RAS interacts with and activates RAF kinases (ARAF, BRAF, and CRAF), which subsequently phosphorylate and activate the dual-specificity kinases MEK1 and MEK2. Activated MEK1 and MEK2 then phosphorylate the extracellular signal- regulated kinases ERK1 and ERK2, which translocate to the nucleus to regulate nuclear substrates, including transcription factors, while also phosphorylating cytoplasmic targets to modulate diverse cellular responses. In parallel, RAS–GTP can also interact with the p110 catalytic subunit of PI3K, activating the PI3K signalling pathway. Feedback regulation is mediated by phosphorylation-dependent inhibitory loops: ERK phosphorylates multiple upstream RTKs, adaptor proteins, BRAF, CRAF, and MEK1, to dampen MAPK signalling, and RSK, a downstream effector of ERK, phosphorylates upstream components, including SOS and CRAF, to attenuate pathway output. Additional negative regulators, including phosphatases DUSPs and the inhibitory SPRY and SPRED proteins, modulate RAS and ERK activity to fine- tune signal intensity and duration. The RAS GTPase-activating protein NF1 promotes RAS inactivation by stimulating hydrolysis of GTP to GDP. The scaffold protein KSR facilitates the spatial organisation of the pathway components to enhance signalling efficiency. Clinically approved BRAF inhibitors and MEK inhibitors are indicated. Temporal dynamics of MAPK are shaped by the interplay of feedback loops, scaffold proteins, and phosphatases. Oscillatory ERK signalling, often driven by pulsatile upstream inputs and rapid feedback, is associated with transient gene expression, whereas sustained ERK activation typically results from persistent upstream stimulation or impaired feedback. Phosphorylation events are indicated by circled P symbols; arrows denote activation, and T-shaped lines represent inhibition. Figure created with BioRender.com. DUSPs=dual-specificity phosphatases. 1640 ytivitca KRE ytivitca KRE Receptor tyrosine kinase RAS–GDP P SOS NF1 P P HRAS p85 PI3K KRAS RAS–GTP p110 NRAS Sustained RSK P ARAF BRAFV600 inhibitors • Vemurafenib BRAF RAF • Dabrafenib CRAF • Encorafenib MEK inhibitors • Trametinib Oscillatory P P KSR MEK1 • Cobimetinib MEK MEK2 • Binimetinib • Selumetinib P • Mirdametinib P P ERK1 ERK ERK2 Time DUSP P SPRY SPRED Nuclear substrates Gene Therapeutics thereby activating RAS at the plasma membrane. kinases for ERK1 and ERK2, their own phosphorylation Activated RAS–GTP binds the RAS-binding domain of and activation can be mediated by a diverse array of the RAF family of serine–threonine MAP3Ks (ARAF, MAP3Ks, including mixed-lineage kinases 1–4, MEKK1, BRAF, and CRAF), relieving autoinhibition.14 RAF MEKK3, PAK1, and COT (figure 3).28–32 isoforms dier in intrinsic kinase activity, with BRAF Activated ERK1 and ERK2 proteins directly regulate having the highest activity, followed by CRAF and more than 600 substrates and indirectly influence ARAF.15,16 Membrane recruitment promotes RAF protein approximately 1800 additional targets through diverse dimerisation, either as homodimers or heterodimers mechanisms.33 These mechanisms include (with BRAF–CRAF predominating in RAS-mediated phosphorylation of nuclear transcription factors such as signalling), which is required for full kinase activation.14 Elk1, c-Fos, and members of the Myc family;34–36 stabili- Once activated, RAF proteins phosphorylate and activate sation of target mRNA, such as VEGFR, EGFR, DUSP6, the dual-specific MAPK kinases MEK1 and MEK2 by and CDKN1A, via phosphorylation of RNA-binding targeting serine residues within their activation loop— proteins;37,38 and modulation of chromatin structure and specifically Ser218 and Ser222 in human MEK1.17 MEK1 RNA processing.39 Collectively, ERK-dependent signalling and MEK2 then phosphorylate the terminal MAPKs ERK1 orchestrates global gene expression programmes that and ERK2 on conserved threonine and tyrosine residues govern cell fate decisions, including cell proliferation, within their activation loop, such as Thr202 and Tyr204 in dierentiation, and survival. human ERK1,18 leading to ERK activation (figure 2). MEK and ERK also participate in tightly regulated Although MEK1 and MEK2 serve as the exclusive upstream negative feedback loops that shape the dynamic behaviour S218 S222 T292 T286 S298 NES NRR P-loop ATP Activation MEK1 loop ERK Protein kinase 1 Proline-rich DVD 393 dock domain K57 60 F53 P124 40 Q56 D67 E I1 1 0 0 3 2 C121 G128 E203 20 F129 Y130 RAF S222 S226 NES NRR P-loop ATP Activation MEK2 loop ERK Protein kinase 1 Proline-rich DVD 400 dock domain Figure 3: Human MEK1 and MEK2 protein domains, key regulatory sites, and frequent cancer-associated mutations The multifunctional N-terminal region contains the ERK-binding domain (ERK dock), the NES and the NRR. The central kinase domain includes the glycine rich P-loop, the ATP-binding pocket, the activation loop with the RAF (MAP3K)-targeted serine phosphorylation sites, and the proline-rich domain. Key phosphorylation sites are annotated: activating sites are shown in green and inhibitory sites in red, along with the kinases responsible for their modifications. The C-terminal region features an unstructured DVD motif for binding with upstream MAP3Ks.19 In MEK1, Thr292 is an ERK1-mediated and ERK2-mediated feedback phosphorylation site (absent in MEK2), whereas Ser298 is an activating site phosphorylated by PAK. Below each MEK schema, the frequency and distribution of common cancer-associated mutation sites are shown, and mutation sites linked with BRAF or MEK inhibitor resistance (or both) are in red text.20–22 Cancer-associated mutation frequency was derived from a curated set of non-redundant studies in cBioPortal (95 474 samples).23,24 RASopathy MEK1 and MEK2 variants also cluster near the NRR and amino- terminal region of the kinase domain, and common RASopathy variants are in bold text (data were obtained from the Clinical Genome Resource).25 The schematic design and annotation were informed by literature.8,26,27 Figure created with BioRender.com. CDK=cyclin-dependent kinase. DVD=domain for versatile docking. NES=nuclear export sequence. NRR=negative regulatory region. fo rebmuN fo rebmuN stneitap stneitap RAF CDK1 ERK CDK2 PAK 15 F57 P128 5 A32 V35L46Q60D71 S94 R112 C125 Y134 E207 R231 R303 For Clinical genome see www. clinicalgenome.org Therapeutics of MAPK signalling, often producing transient pulses or 40% of their amino acid identity. These structural oscillation patterns of activity rather than sustained dierences contribute to distinct biological functions. activation (figure 2).40,41 Activated ERK1 and ERK2 MEK1, but not MEK2, forms complexes with CRAF and phosphorylate multiple upstream components, including contains a unique phosphorylation site at Thr292 that RTKs (eg, EGFR, HER2, and ERBB3), adaptor proteins mediates ERK-dependent feedback, a regulatory feature (eg, GAB2, FRS2, IRS1, and IRS2), the RAS guanine absent in MEK2. Functional divergence is underscored nucleotide exchange factor SOS, RAF kinases (eg, BRAF by genetic studies: MEK2 knock-out mice are viable and and CRAF), and MEK1,42–44 to rapidly dampen MAPK phenotypically normal, whereas MEK1 deletion results in intensity and duration.7,45,46 In addition to this immediate embryonic lethality.53 attenuation, ERK activation induces delayed but sustained To date, the US Food and Drug Administration (FDA) pathway suppression through transcriptional upregulation has approved five MEK inhibitors: trametinib, of negative regulators, including the SPRY and SPRED cobimetinib, binimetinib, selumetinib, and mirdametinib. proteins and dual-specificity phosphatases (DUSPs). These agents are ATP non-competitive inhibitors that DUSPs selectively dephosphorylate and inactivate ERK, bind to a unique allosteric site adjacent to the ATP site thus terminating MAPK signalling, whereas SPRY and (figure 3). This interaction stabilises MEK1 and MEK2 in SPRED proteins inhibit RAS and RAF activation their naturally inactive conformation,54 which results in (figure 2).43,47 Downstream ERK eectors, such as the potent inhibition at nanomolar concentrations (table 1). ribosomal S6 kinases, also reinforce negative feedback by The high target specificity of these inhibitors57 is attributed phosphorylating and inhibiting upstream components, to the complete sequence identity of the allosteric binding including SOS and RAF, thereby constraining the sites of MEK1 and MEK2, and the limited sequence and amplitude and duration of ERK activity (figure 2).48 These structural conservation of this allosteric pocket across the feedback mechanisms are essential for maintaining broader kinome.54,58 MAPK pathway homoeostasis and preventing aberrant MEK inhibitors have greatest clinical ecacy in cellular proliferation and dierentiation. tumours with BRAFV⁶⁰⁰ mutations, in which the MAPK MAPK signalling is also regulated by the KSR family of pathway is constitutively active and less susceptible to scaold proteins, which function as downstream feedback reactivation. In this context, RAS and CRAF eectors of RAS. KSR proteins physically interact with all activity is typically lower than in RAS-driven or RTK- three kinases in the kinase cascade; MEK is constitutively driven tumours.59 By contrast, in tumours with BRAFWT, bound, whereas RAF and ERK associate in a stimulus- non-V600 BRAF mutations,60 or NF1 loss-of-function dependent manner (figure 2). This dynamic scaolding mutations,61 and in tumours driven by oncogenic RAS or facilitates the spatial and temporal assembly of kinase activated RTKs, MEK inhibitors show little and variable complexes, thereby enhancing signal fidelity and ecacy. This low sensitivity is largely due to MEK propagation.49 Disruption of these regulatory mechan- inhibitor-induced relief of ERK-dependent negative isms, whether through genetic mutation or dysregulation, feedback on RAF, which promotes RAF dimerisation contributes to pathological hyperactivation of MAPK and activation. The resulting paradoxical, RAF-dependent signalling, a hallmark of cancer and developm ental phosphorylation of MEK1 and MEK2 leads to reactivation disorders. of ERK1 and ERK2 signalling62 and thereby undermines the inhibitory eects of MEK-targeted therapies. Targeting MEK in cancer: mechanistic and Consequently, complete and durable suppression of biological rationale MAPK signalling remains challenging in tumours driven MEK1 and MEK2 share more than 80% of their amino by upstream activators such as RAS mutations or RTK acid identity and possess a highly conserved overall activation, and MEK inhibitor monotherapy has not structure, including a flexible N-terminal domain with produced meaningful clinical responses in these three key elements: an ERK docking region, a nuclear settings.63–65 In the NEMO trial, a modest improvement in export signal, and an inhibitory segment that stabilises progression-free survival was observed with the MEK the kinase in its inactive confirmation. The central inhibitor binimetinib versus dacarbazine in patients with protein kinase domain contains the kinase activation NRASmut melanoma (median progression-free survival loop and a proline-rich domain with multiple activating 2·8 months vs 1·5 months; hazard ratio [HR] 0·62 and inhibitory phosphorylation sites. Activation of MEK [95% CI 0·47–0·80]), although this benefit did not requires MAP3K-mediated phosphorylation of translate into a survival advantage.66 Even newer- two conserved serine residues (Ser218 and Ser222 in generation MEK inhibitors, such as trametinib and human MEK1). The C-terminal sequence of MEK cobimetinib, which not only inhibit the catalytic activity contains a 20 amino acid-docking motif essential for of MEK but also reduce rebound activation by disrupting specific interactions with upstream MAP3Ks RAF–MEK complex formation, remain less potent in (figure 3).19,50–52 Although the MEK1 and MEK2 kinase BRAFWT tumours.62,63 Similarly, in the METRIC trial, the domains are highly similar, they diverge in their MEK inhibitor trametinib improved progression-free N-terminal and proline-rich domains, which share only survival compared with dacarbazine chemotherapy 1642 Therapeutics Trametinib Cobimetinib Binimetinib Selumetinib Mirdametinib Biopharmaceutics Class II Class I Class IV Class IV Class I classification system class In vitro MEK1 IC =0·7 nM; MEK1 IC =0·95 nM; MEK1 IC =12 nM; MEK1 IC =10–14 nM MEK1 IC =1 nM; 50 50 50 50 50 enzyme55,56 MEK2 IC =0·9 nM MEK2 IC =199 nM MEK2 IC =46 nM MEK2 IC =1 nM 50 50 50 50 Recommended 2 mg once a day 60 mg once a day, for 21 days of 45 mg twice a day 25 mg/m² twice a day 2 mg/m² twice a day, for dosage a 28-day cycle followed by 7 days 21 days of a 28-day cycle of no treatment followed by 7 days of no treatment Elimination half-life 4–5 days 43·6 h 3·5 h 6·2 h 28 h Peak time 1·5 h 2·4 h 1·5 h 1 h 0·8 h Plasma clearance 5·4 L/h 13·8 L/h 20·2 L/h 8·8 L/h 6·3 L/h Approved Monotherapy: unresectable or Monotherapy: histiocytic Combination (with Monotherapy: paediatric, Monotherapy: adult and indications metastatic BRAFV⁶⁰⁰E and BRAFV⁶⁰⁰K neoplasms (eg, Erdheim–Chester encorafenib): unresectable or symptomatic, inoperable paediatric patients (≥2 years) melanoma (2013); combination disease and Langerhans cell metastatic BRAFV⁶⁰⁰E and neurofibromatosis with neurofibromatosis type 1 (with dabrafenib): unresectable or histiocytosis; 2022); BRAFV⁶⁰⁰K melanoma (2018), type 1-related plexiform who have symptomatic metastatic BRAFV⁶⁰⁰E and BRAFV⁶⁰⁰K combination (with and BRAFV⁶⁰⁰E metastatic neurofibromas (2020) plexiform neurofibromas not melanoma (2014), BRAFV⁶⁰⁰E vemurafenib): unresectable or NSCLC (2023) amenable to complete NSCLC (2017), adjuvant BRAFV⁶⁰⁰E metastatic BRAFV⁶⁰⁰E and BRAFV⁶⁰⁰K resection (2025) and BRAFV⁶⁰⁰K-mutant melanoma melanoma (2015); triplet (2018), BRAFV⁶⁰⁰E anaplastic therapy (cobimetinib + thyroid cancer (2018), vemurafenib + atezolizumab): and BRAFV⁶⁰⁰E solid tumours metastatic BRAFV⁶⁰⁰E and BRAFV⁶⁰⁰K (2022) melanoma (2020) Common adverse Fatigue, nausea, rash, diarrhoea, Fatigue, nausea, rash, diarrhoea, Fatigue, nausea, rash, Fatigue, nausea, diarrhoea, Fatigue, nausea, vomiting, rash, reactions myalgia, peripheral oedema, and photosensitivity, peripheral diarrhoea, and peripheral oedema, acneiform dermatitis, diarrhoea, and creatine kinase acneiform dermatitis oedema, and acneiform oedema and asymptomatic creatine elevation dermatitis kinase elevation Class I refers to high solubility and high permeability, class II refers to low solubility and high permeability, class III refers to high solubility and low permeability, and class IV refers to low solubility and low permeability. Dabrafenib, vemurafenib, and encorafenib are selective inhibitors of BRAFV⁶⁰⁰-mutant kinases; atezolizumab is an anti-PD-L1 immune checkpoint inhibitor. Approved indications accessed from the US FDA. FDA=Food and Drug Administration. IC =half maximal inhibitory concentration. NSCLC=non-small-cell lung cancer. Table 1: MEK inhibitors approved by the US FDA for clinical use (median 4·9 months vs 1·5 months; HR 0·54 [95% CI have shown on-target ERK suppression and early clinical 0·41–0·60]) in patients with BRAFV⁶⁰⁰E (ie, Val600Glu)- activity, including in tumours resistant to RAF or MEK mutant or BRAFV⁶⁰⁰K (ie, Val600Lys)-mutant melanoma, inhibitors,71 although most remain in early-phase trials. establishing MEK inhibition as clinically active but SHP2 inhibitors (eg, RMC-4630 and TNO155)72 and the inferior to BRAF-targeted approaches.67,68 SOS1 inhibitor BI-170196373 are being evaluated both as A notable exception to MEK inhibitor limitations is monotherapy and in combination with other agents, observed in paediatric patients with neurofibromatosis including MEK inhibitors. Several trials with BI-1701963 type 1-associated plexiform neurofibromas, in whom have been terminated due to toxicity.73 These approaches MEK inhibition with selumetinib monotherapy induces highlight ongoing eorts to target multiple nodes of clinically meaningful tumour regression, with 17 (71%) of MAPK signalling to improve durable responses in the 24 patients in the trial having confirmed partial patients with MAPK-driven cancers. response (table 1).69 Neurofibromatosis type 1 is caused by germline loss-of-function mutations in the NF1 gene, Overcoming BRAF-inhibitor resistance and which encodes a key negative regulator of RAS, and toxicity: the central role of MEK inhibition benign tumours develop following somatic loss of the Selective BRAF inhibitors were the first targeted therapies remaining wild-type NF1 allele. The favourable response to show a survival benefit in patients with BRAFV⁶⁰⁰- to MEK inhibition in these tumours is likely to reflect mutant melanoma. FDA-approved selective BRAFV⁶⁰⁰ their genetic stability and a paucity of additional inhibitors, including vemurafenib, dabrafenib, and oncogenic mutations beyond this somatic loss.69,70 encorafenib, act by binding the ATP-binding pocket of In parallel, additional inhibitors targeting MAPK mutant BRAF proteins, eectively targeting BRAFV⁶⁰⁰E, signalling, including ERK inhibitors, which act BRAFV⁶⁰⁰D (ie, Val600Asp), BRAFV⁶⁰⁰R (ie, Val600Arg), and downstream of MEK to block ERK-mediated transcription BRAFV⁶⁰⁰K variants.74–76 In patients with advanced and feedback; SHP2 inhibitors, which prevent RAS BRAFV⁶⁰⁰-mutant melanoma, these inhibitors significantly activation by RTKs; and SOS1 inhibitors, which disrupt improve objective response rates (ORRs), progression-free the GRB2–SOS complex, are under investigation. First- survival, and overall survival compared with dacarbazine in-class ERK inhibitors, such as ulixertinib (BVD-523), (table 2).89,90 For example, in the BRIM-3 trial of patients Therapeutics with treatment-naive BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K- overall survival of 13·6 months (12·0–15·4) mutant melanoma, patients treated with vemurafenib had versus 9·7 months (7·9–12·8).89–91 Notably, vemurafenib is a median progression-free survival of 6·9 months (95% CI approved only for patients with BRAFV⁶⁰⁰E mutations. In 6·1–7·0), compared with 1·6 months (1·6–2·1) in patients contrast, dabrafenib has shown clinical activity across a treated with dacarbazine chemotherapy, and a median broader spectrum of BRAF variants (including BRAFV⁶⁰⁰E, n Study focus ORR, % (95% CI) Median progression- Median overall free survival, months survival, months (95% CI) (95% CI) METRIC, Flaherty et al (2012)67,68 Trametinib 214 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant metastatic 40% (33·6–47·1) 4·9 (NR) 15·6 (NR) melanoma Dacarbazine or paclitaxel 108 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant metastatic 14% (8·0–21·9) 1·5 (NR) 11·3 (NR) melanoma Combi-d, Long et al (2014)77,78 Trametinib + dabrafenib 211 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant metastatic 69% (62–75) 11·0 (8·0–13·9) 25·1 (19·2 to not melanoma reached) Placebo + dabrafenib 212 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant metastatic 53% (46–60) 8·8 (5·9–9·3) 18·7 (15·2–23·7) melanoma coBRIM, Ascierto et al (2015)79,80 Cobimetinib + vemurafenib 247 Untreated locally advanced or metastatic 70% (63·5–75·3) 12·3 (9·5–13·4) 22·3 (20·3 to not estimable) Placebo + vemurafenib 248 BRAFV⁶⁰⁰-mutant melanoma 50% (43·6–56·4) 7·2 (5·6–7·5) 17·4 (15·0–19·8) NEMO, Dummer et al (2017)66 Binimetinib 269 NRASmut unresectable or metastatic melanoma 41% (11–20) 3·0 (2·8–4·1) 11·0* (8·9–13·6) Dacarbazine 133 NRASmut unresectable or metastatic melanoma 9% (3–13) 1·8 (1·5–2·8) 10·1* (7·0–16·5) SUMIT, Carvajal et al (2018)81 Selumetinib + dacarbazine 97 Metastatic uveal melanoma 3% (NR) 2·8* (NR) NR Placebo + dacarbazine 32 Metastatic uveal melanoma 0% (NR) 1·8* (NR) NR BEACON, Kopetz et al (2019)82 Binimetinib + encorafenib + cetuximab 222 BRAFV⁶⁰⁰E-mutant colorectal cancer 26% (18–35) 4·3 (4·1–5·2) 9·0 (8·0–11·4) Encorafenib + cetuximab 216 BRAFV⁶⁰⁰E-mutant colorectal cancer 20% (13–29) 4·2 (3·7–5·4) 8·4 (7·5–11·0) Investigator choice 193 BRAFV⁶⁰⁰E-mutant colorectal cancer 2% (0–7) 1·5 (1·5–1·7) 5·4 (4·8–6·6) Combi-v, Robert et al (2019)83 Trametinib + dabrafenib 352 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant metastatic 64% (59–61) 11·4 (NR) NR melanoma Vemurafenib 352 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant metastatic 51% (46–57) 7·3 (NR) 17·2 (NR) melanoma IMblaze370, Eng et al (2019)84 Cobimetinib + atezolizumab 183 Microsatellite-stable metastatic colorectal cancer 3% (0·9–6·3) 1·91* (1·87–1·97) 8·87* (7·00–10·61) Atezolizumab 90 Microsatellite-stable metastatic colorectal cancer 2% (0·3–7·8) 1·94* (1·91–2·10) 7·10* (6·05–10·05) Regorafenib 90 Multikinase inhibitor microsatellite-stable 2% (0·3–7·8) 2·00 (1·87–3·61) 8·51 (6·41–10·71) metastatic colorectal cancer COLUMBUS, Dummer et al (2020)85,86 Binimetinib + encorafenib 192 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant melanoma 64·1% (56·8–70·8) 14·9 (11·0–20·2) 33·6 (24·4–39·2) Encorafenib 194 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant melanoma 51·5% (44·3–58·8) 9·6 (7·4–14·8) 23·5 (19·6–33·6) Vemurafenib 191 BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant melanoma 40·8% (33·8–48·2) 7·3 (5·6–7·9) 16·9 (14·0–24·5) IMspire170, Gogas et al (2021)87 Cobimetinib + atezolizumab 222 BRAFV⁶⁰⁰-negative melanoma 26·0% (20·1–32·6) 5·5* (3·8–7·2) NR Pembrolizumab 224 BRAFV⁶⁰⁰-negative melanoma 31·6% (25·3–38·4) 5·7* (3·7–9·6) NR IMspire150, Ascierto et al (2023)88 Cobimetinib + vemurafenib + atezolizumab 160 BRAFV⁶⁰⁰E-mutant melanoma 67% (61–72) 15·1 (11·4–18·4) 39·0 (29·9 to not estimable) Cobimetinib + vemurafenib + placebo 170 BRAFV⁶⁰⁰E-mutant melanoma 65% (59–71) 10·6 (9·3–12·7) 25·8 (22·0–34·6) NR=not reported. ORR=objective response rate. *Did not meet statistical significance. Table 2: Selected phase 3 clinical trials evaluating MEK inhibitors (monotherapy and combination) 1644 Therapeutics BRAFV⁶⁰⁰K, and BRAFK⁶⁰¹E [ie, Lys601Glu]), which supports the incidence of high-grade cutaneous squamous cell its wider therapeutic applications.92 Encorafenib has carcinoma to be 11·6% (95% CI 9·8–13·8) in patients similarly shown ecacy across multiple BRAFV⁶⁰⁰ treated with single-agent BRAF inhibitors, compared variants.85 Despite these improvements, response with 2·8% (95% CI 1·9–4·0) in patients receiving durability remains low and highly variable. Analysis of combined BRAF–MEK inhibitor therapy.115 Thus, BRAF– 135 metastatic lesions from 24 patients showed that MEK inhibitor combination therapy has become standard only 71 (53%) had a complete response to BRAF inhibitor of care for BRAFV⁶⁰⁰-mutant melanoma as it delays monotherapy.93 These findings highlight that BRAF acquired resistance, increases progression-free survival inhibitor mono therapy is insucient for durable disease and overall survival, and reduces the risk of secondary control, which probably reflects rapid adaptive resistance skin neoplasms. Three BRAF–MEK inhibitor with MAPK pathway reactivation and tumour combinations have received US FDA approval: heterogeneity. These results emphasise the need for more dabrafenib plus trametinib, vemurafenib plus eective therapeutic combination strategies to improve cobimetinib, and encorafenib plus binimetinib (table 2). long-term outcomes.89,94,95 The phase 3 COMBI-d and COMBI-v trials evaluated Resistance to BRAF inhibitors is a major therapeutic first-line treatment with the BRAF inhibitor dabrafenib challenge in the treatment of BRAFV⁶⁰⁰-mutant cancers. and the MEK inhibitor trametinib in patients with Tumour subclones resistant to BRAF inhibition often pre- advanced BRAFV⁶⁰⁰E-mutant or BRAFV⁶⁰⁰K-mutant exist, particularly within larger metastatic lesions, and melanoma.77,83,113 Both trials showed that the combination expand under the selective pressure of treatment.93,96–98 of BRAF and MEK inhibitors was associated with Most resistance mechanisms converge on the reactivation superior outcomes compared with BRAF inhibitor of ERK signalling despite BRAF inhibition. These monotherapy. Pooled analyses of patients treated with resistance mechanisms include the upregulation of RTKs dabrafenib and trametinib from the COMBI-d and (eg, IGF1R, EGFR, and PDGFR-ß), activating RAS COMBI-v trials showed a median progression-free mutations, BRAF amplification or alternative splicing, survival of 11·1 months (95% CI 9·5–12·8), median and mutations in MEK1 or MEK2.22,99,100 Importantly, a overall survival of 25·9 months (22·6–31·5), and ORR subset of BRAF inhibitor resistance mechanisms are of 68% (64–72).113 An initial phase 2 randomised study sensitive to downstream inhibition at the MEK1 or MEK2 indicated that higher doses of trametinib combined with nodes or the ERK1 or ERK2 nodes.101,102 For instance, dabrafenib yielded improved outcomes compared with tumours with BRAF splice variants, BRAF copy number half the recommended monotherapy dose for both gains, MEK1 mutations, RAS mutations, or elevated dabrafenib and trametinib, and underscores the PDGFR-β expression are resistant to BRAF inhibitors but importance of optimised dosing in combination have some sensitivity to MEK inhibitors, ERK inhibitors, regimens.116,117 Subsequently, the BRAF–MEK inhibitor or combination BRAF–MEK inhibitor therapy.103,104 The combinations vemurafenib plus cobimetinib and recurrent reactivation of ERK signalling in BRAF encorafenib plus binimetinib showed improved ecacy inhibitor-resistant tumours thus provides a compelling compared with vemurafenib mono therapy and rationale for MEK inhibition, oering a potential strategy encorafenib monotherapy, respectively.85,114,118 The phase 3 to overcome resistance and enhance clinical outcomes. COLUMBUS trial directly compared encorafenib plus Another key limitation of BRAF inhibitor monotherapy binimetinib with encorafenib or vemurafenib is the paradoxical activation of ERK signalling in BRAFWT monotherapy in patients with BRAFV⁶⁰⁰-mutant keratinocytes, which promotes the development of melanoma and found a median progression-free survival cutaneous squamous cell carcinoma and keratoacanthoma of 14·9 months (95% CI 11·0–20·2) with the in 20–26% of patients with melanoma treated with combination, 9·6 months (7·4–14·8) with encorafenib vemurafenib90,105 and 6–11% of patients with melanoma alone, and 7·3 (5·6–7·9) months with vemurafenib.85 At treated with dabrafenib.92,106,107 Cutaneous squamous cell 7-year follow-up, median melanoma-specific survival carcinoma lesions typically arise within 2–4 months of was longest in patients with the combination BRAF inhibitor treatment108 and frequently harbour (36·8 months [27·7–51·5]), followed by encorafenib genetic alterations in RAS GTPases.109 Paradoxical ERK monotherapy (24·2 months [19·9–35·7]) and activation in BRAFWT or RASmut cells occurs through RAF vemurafenib monotherapy (19·3 months [14·8–25·9]), dimerisation wherein binding of the BRAF inhibitor to and 21·2% of patients remained progression free.86 one RAF protomer induces the transactivation of the Beyond melanoma, the dabrafenib–trametinib partner protomer,104,110,111 or by relief of autoinhibitory RAF combination has shown activity in other BRAFV⁶⁰⁰- phosphorylation.112 This sustained RAF activation mutant cancers, including anaplastic thyroid cancer maintains ERK signalling despite BRAF inhibition, con- (ORR 69% [95% CI 41–89]), non-small-cell lung tributing to the formation of cutaneous squamous cell carcinoma (ORR 64% [46–79]), and biliary tract cancer carcinoma and the progression of RASmut cancers. (ORR 47% [31–62]).119–121 Combined BRAF and MEK inhibition mitigates Early-phase clinical studies of the pan-RAF inhibitor paradoxical ERK activation.113,114 A meta-analysis reported naporafenib in combination with the MEK inhibitor Therapeutics trametinib have shown clinically meaningful activity in dose-limiting toxic eects, including elevated serum patients with NRASmut melanoma, with an ORR of 46·7% lipase and creatinine phosphokinase concent rations.127 (95% CI 21·3–73·4) and median progression-free survival Combinations of MEK inhibitors with dual CDK4 and of 5·52 months at the recommended dose.122 Anti-tumour CDK6 inhibitors, including trametinib plus ribociclib, activity of this combination was low in patients with non- binimetinib plus ribociclib, and triple BRAF–MEK– small-cell lung cancer (NSCLC), with only two patients CDK4 and CDK6 inhibition therapy with encorafenib, with KRASmut tumours having a partial response.123 binimetinib, and ribociclib, have also been investigated Similarly, patients receiving naporafenib with anti-PD-1 in patients with NRASmut or BRAFmut melanoma. For therapy (spartalizumab) showed little but notable response, example, trametinib combined with the dual CDK4 and including one complete response and three partial CDK6 inhibitor palbociclib has shown synergistic activity responses in NRASmut melanoma and KRASmut NSCLC in RASmut cancers by concurrently targeting mitogenic expansion cohorts, supporting more investigation of signalling and cell cycle progression.128–130 These pan-RAF combinations.124 Other novel pan-RAF dimer combinations have shown manageable safety profiles, inhibitors, such as belvarafenib and brimarafenib, are although toxicity increases with the number of drugs. being explored in combination with MEK inhibitors; in a Early signs of clinical activity have been observed,131–133 phase 1b trial, cobimetinib plus belvarafenib showed with an ORR of 52·4% reported for the triplet regimen.131 acceptable tolerability and a 38·5% response rate in More studies are required to establish the ecacy of patients with NRASmut melanoma,125 whereas the MEK inhibitor-based combination therapies. combination of brimarafenib with mirdametinib in Another promising approach in targeting MAPK patients with advanced solid tumours was limited by activation is the RAF–MEK clamp inhibitor avutometinib tolerability concerns in another trial, which was terminated, (VS-6766), which simultaneously inhibits MEK1 and highlighting challenges in safely combining these agents MEK2 kinase activity and prevents compensatory MEK (NCT05580770). reactivation by RAF. In combination with the FAK Although the combination reduces paradoxical ERK- inhibitor defactinib, avutometinib has shown durable driven cutaneous toxic eects, some systemic adverse objective responses (44% in KRASmut and 17% in KRASWT events—including fever, vomiting, and diarrhoea—are low-grade serous ovarian cancer134), with accelerated US more frequent and can be more severe than with single- FDA approval granted in May, 2025, for adults with agent BRAF-inhibitor therapy, reflecting additive eects KRASmut recurrent low-grade serous ovarian cancer who of both drugs.77,83,114 Fever is particularly common in have received previous therapy. This approval marks a patients taking dabrafenib plus trametinib, occurring in potential new standard for a rare tumour type with 51–53% patients (any grade) compared with 28% of historically few treatment options. patients treated with dabrafenib monotherapy and 73 Beyond targeted therapy, MEK inhibition has also been (21%) of 349 patients treated with vemurafenib explored in immunotherapy combinations. Preclinical monotherapy.77,83 Although most adverse events are studies suggest that MEK inhibitors can increase tumour manageable with dose reductions or treatment immunogenicity by upregulating major histoc om- interruptions, less than 10% of patients have ongoing patibility complex class I expression, reducing toxic eects, most commonly arthralgias and myalgias, im muno suppressive cytokine production, and promoting with BRAF–MEK inhibitors.126 Overall, the benefit–risk CD8+ T-cell infiltration in the tumour micro enviro- profile continues to favour combination therapy in nment.135–137 These observations provided a rationale for patients with BRAFV⁶⁰⁰-mutant melanoma. combining MEK inhibitors with immune checkpoint inhibitors. In a multicohort phase 1b study of cobimetinib Beyond BRAF: emerging combination strategies plus the anti-PD-L1 antibody atezolizumab, 152 patients with MEK inhibitors with advanced solid tumours, including colorectal cancer, Although MEK inhibitors have shown the greatest melanoma, and NSCLC were treated.138 Confirmed clinical success in combination with BRAF inhibitors in responses were observed in nine (41%) of 22 patients BRAFV⁶⁰⁰-mutant melanoma, ongoing eorts aim to with melanoma, five (18%) of 28 patients with NSCLC, broaden their utility through rational combination and three (19%) of 16 patients with other tumours strategies that target parallel signalling pathways or (including ovarian cancer, clear-cell sarcoma, and renal exploit tumour immunogenicity. Given frequent coa cti- cell carcinoma).138 Activity was noted even in vation of the MAPK and PI3K–AKT–mTOR pathways in microsatellite-stable colorectal cancer, which is typically cancer, and the fact that RAS–GTP also directly activates refractory to immunotherapy, suggesting that MEK PI3K (figure 2), concurrent inhibition of both pathways inhibition might sensitise otherwise immunologically has been explored. In a phase 1b trial, the MEK inhibitor cold tumours to immuno therapy.138–140 cobimetinib was evaluated in combination with the PI3K Building on these findings, the triplet combination of inhibitor pictilisib (GDC-0941) in patients with advanced the MEK inhibitor cobimetinib, the BRAF inhibitor solid tumours.127 Although pharmac odynamic activity vemurafenib, and the PD-L1 inhibitor atezolizumab was was observed, clinical benefit was limited by evaluated in the phase 3 IMspire150 trial in 1646 Therapeutics treatment-naive patients with BRAFV⁶⁰⁰-mutant melanoma.88,141 The median progression-free survival was Drug action Study focus 15·1 months (95% CI 11·4 to 18·4) in the atezolizumab Sullivan et al (2015),130 phase 1/2, completed group versus 10·6 months (9·3 to 12·7) in the control Trametinib MEK inhibition Advanced solid tumours group, and the median overall survival was 39·0 months Palbociclib CDK4 and CDK6 inhibition Advanced solid tumours (29·9 to not estimable) in the atezolizumab group versus Carter et al (2016),147 phase 2, completed 25·8 months (22·0 to 34·6) in the control group, which Selumetinib MEK inhibition Metastatic pancreatic led to US FDA approval in July, 2020.88,141 However, adenocarcinoma statistically significant ecacy of this strategy was not Erlotinib EGFR inhibition Metastatic pancreatic shown in two other phase 3 melanoma trials adenocarcinoma (KEYNOTE-022 and COMBI-i) and has not been Lee et al (2016),128 phase 1, completed replicated across other tumour types.142,143 In the Binimetinib MEK inhibition KRASmut and NRASmut colorectal cancer IMblaze370 phase 3 clinical trial, the combination of cobimetinib plus atezolizumab was investigated in Palbociclib CDK4 and CDK6 inhibition KRASmut and NRASmut colorectal cancer patients with previously treated microsatellite-stable Ascierto et al (2017),131 phase 1, completed colorectal cancer, but did not show a statistically signifi- Binimetinib MEK inhibition Advanced solid tumours cant overall survival benefit over regorafenib, a Encorafenib BRAF inhibition Advanced solid tumours small-molecule multikinase inhibitor.84,139 Similarly, Ribociclib CDK4 and CDK6 inhibition Advanced solid tumours binimetinib has been explored in combination with Algazi et al (2018),148 phase 2, completed immune checkpoint inhibitors, including pembro- lizumab, nivolumab, and ipilimumab, in patients with Trametinib MEK inhibition BRAFWT and NRASWT wild-type melanoma advanced solid tumours, such as melanoma and GSK2141795 AKT inhibition BRAFWT and NRASWT wild-type colorectal cancer, reflecting continued eorts to identify melanoma synergistic interactions, optimise combination strategies, Bendell et al (2020),149 phase 1/2, completed and improve biomarker-driven patient selection.144–146 Cobimetinib MEK inhibition EGFRmu tNSCLC In addition to immunotherapy, MEK inhibitors are Osimertinib EGFR inhibition EGFRmu tNSCLC being tested in combination with other therapeutic RMC-4630 SHP2 inhibition EGFRmu tNSCLC classes, such as antiangiogenic and apoptotic agents. Gaudreau et al (2020),150 phase 1/2, completed Multiple clinical trials are underway to assess the safety Selumetinib MEK inhibition NSCLC and ecacy of these combinations across diverse tumour Durvalumab Anti-PD-L1 immune checkpoint NSCLC types (table 3). inhibition Tremelimumab Anti-CTLA-4 immune checkpoint NSCLC MEK pathway modulation beyond oncology inhibition Although MEK inhibitors were originally developed and LoRusso et al (2020),132 phase 1, terminated per sponsor decision used for oncological indications, evidence increasingly Trametinib MEK inhibition Advanced solid tumours suggests that aberrant MAPK signalling contributes to Ribociclib CDK4 and CDK6 inhibition Advanced solid tumours the pathogenesis of several non-malignant conditions. Schuler et al (2022),133 phase 1/2, completed As a result, MEK inhibitors are being repurposed or Binimetinib MEK inhibition NRASmut melanoma investigated for use in a range of inflammatory, fibrotic, Ribociclib CDK4 and CDK6 inhibition NRASmut melanoma and developmental disorders driven by dysregulated Buchbinder et al (2023),151 phase 1/2, completed RAS–RAF–MEK–ERK signalling.161 Dabrafenib BRAF inhibition Melanoma post-BRAF– MEK RASopathies have been among the first non-cancer inhibitor progression indications to benefit from targeted MEK inhibition.162–165 Trametinib MEK inhibition Melanoma post-BRAF– MEK In April, 2020, selumetinib became the first MEK inhibitor inhibitor progression approved outside of oncology, receiving US FDA approval MCS110 CSF-1 inhibition Melanoma post-BRAF– MEK inhibitor progression for paediatric patients with symptomatic neurofibromatosis Manji et al (2023),152 phase 1/2, terminated due to toxicity and lack of efficacy type 1-associated plexiform neurofibromas. This approval was based on the phase 2 SPRINT trial, which showed a Cobimetinib MEK inhibition KRASmut malignancies partial response in 34 (68%) of 50 patients alongside Atezolizumab Anti-PD-L1 immune checkpoint KRASmut malignancies inhibition improvement in pain and functional outcomes.69,166 Beyond Hydroxychloroquine Autophagy inhibition KRASmut malignancies neuro fibro matosis type 1, case reports also describe Schjesvold et al (2023),153 phase 1/2, completed trametinib-mediated reversal of severe hypertrophic Cobimetinib MEK inhibition Multiple myeloma cardiomyopathy and resolution of chylous eusions in Atezolizumab Anti-PD-L1 immune checkpoint Multiple myeloma children with Noonan syndrome (caused by germline inhibition mutations in genes such as PTPN11, SOS, and RAF1), Venetoclax BCL-2 inhibition Multiple myeloma illustrating the potential for broader applications across (Table 3 continues on next page) RASopathy phenotypes.167–169 Therapeutics Somatic activation of mutations in MEK pathway genes, particularly KRAS and MAP2K1, have also been identified in arteriovenous malformations.170,171 Preclinical Drug action Study focus studies implicate excessive MEK signalling in endothelial (Continued from previous page) dysregulation and abnormal vessel morphogenesis. Tian et al (2023),154 phase 2, completed Although clinical experience remains rare, trametinib Dabrafenib BRAF inhibition BRAFV⁶⁰⁰E -mutant colorectal cancer has shown promise in inducing regression and sym- Trametinib MEK inhibition BRAFV⁶⁰⁰E -mutant colorectal cancer ptomatic improvement of extracranial arteriovenous Spartalizumab Anti-PD-1 immune checkpoint BRAFV⁶⁰⁰E-mutant colorectal cancer malformations and in managing capillary malformation– inhibition arteriovenous malformation syndrome with cardiac Van Cutsem et al (2023),155 phase 2, completed compromise.172,173 Binimetinib MEK inhibition BRAFV⁶⁰⁰E-mutant colorectal cancer Fibrotic diseases represent another promising avenue Encorafenib BRAF inhibition BRAFV⁶⁰⁰E-mutant colorectal cancer for MEK inhibitor repurposing. Aberrant MEK signalling Cetuximab EGFR inhibition BRAFV⁶⁰⁰E-mutant colorectal cancer promotes fibroblast proliferation, extracellular matrix Manoharan et al (2024),156 phase 2, completed deposition, and production of inflammatory mediators, Cobimetinib MEK inhibition Platinum-resistant high-grade which are key processes in the development of fibrotic serous ovarian cancer diseases.174 In preclinical models, MEK inhibition with Atezolizumab Anti-PD-L1 immune checkpoint Platinum-resistant high-grade inhibition serous ovarian cancer PD 0325901 and trametinib reduced fibrosis in lung and Bevacizumab VEGF inhibition Platinum-resistant high-grade liver injury.175,176 Clinical trials are in early stages, but MEK serous ovarian cancer inhibitors are under investigation in idiopathic Mutch et al (2024),157 phase 1, completed pulmonary fibrosis and systemic sclerosis.174,177 Cobimetinib MEK inhibition BRCAWT ovarian cancer Hyperactivation of MAPK signalling has been Atezolizumab Anti-PD-L1 immune checkpoint BRCAWT ovarian cancer implicated in the pathogenesis of several autoimmune inhibition and inflammatory diseases, including rheumatoid Niraparib PARP inhibition BRCAWT ovarian cancer arthritis, psoriasis, and inflammatory bowel disease.178–181 Somaiah et al (2024),158 phase 2, completed MEK inhibition has been shown to modulate cytokine Selumetinib MEK inhibition Malignant peripheral nerve sheath production, reduce T-cell activation, and impair pro- tumours inflammatory signalling in preclinical models;135 however, Sirolimus mTOR inhibition Malignant peripheral nerve sheath the systemic inhibition of MEK in chronic inflam matory tumours settings poses substantial toxicity concerns, and no MEK Dagogo-Jack et al (2025),159 phase 1/2, active, not recruiting inhibitor has yet been approved for these indications. Cobimetinib MEK inhibition ALK-rearranged NSCLC In gynaecological disorders, deep infiltrating endo- Alectinib ALK inhibition ALK-rearranged NSCLC metriosis, a benign yet frequently debilitating condition, Prasath et al (2025),160 phase 2, completed has been shown to harbour somatic mutations in Trametinib MEK inhibition Triple negative breast cancer oncogenic drivers, such as KRAS and PIK3CA.182 These GSK2141795 AKT inhibition Triple negative breast cancer genetic alterations converge on the PI3K–AKT–mTOR NCT03272464, phase 1, terminated due to slow accrual and MEK–ERK signalling pathways, implicating aberrant Dabrafenib BRAF inhibition BRAFV⁶⁰⁰E-mutant orB RAFV⁶⁰⁰K- pathway activation in both lesion proliferation and mutant melanoma and solid tumours chronic inflammation. Preclinical data suggest that Trametinib MEK inhibition BRAFV⁶⁰⁰E-mutant orB RAFV⁶⁰⁰K- targeted inhibition of these pathways might attenuate mutant melanoma and solid disease progression and symptom burden; however, tumours clinical studies are scarce.183–185 Itacitinib JAK1 inhibition BRAFV⁶⁰⁰E-mutant orB RAFV⁶⁰⁰K- mutant melanoma and solid Challenges and limitations of MEK inhibitor tumours therapy NCT03631953, phase 1, recruiting Drug resistance Trametinib MEK inhibition Refractory meningiomas Despite early promise, MEK inhibitors have shown little Alpelisib PIK3CA inhibition Refractory meningiomas and often non-durable clinical activity across most tumour NCT03947385, phase 1/2, recruiting types. Whereas combination strategies, particularly with Binimetinib MEK inhibition GNAQ, GNA11, or PRKC fusion solid tumours BRAF inhibitors, oer improved outcomes in some Darovasertib PKC inhibition GNAQ, GNA11, or PRKC fusion populations, dual BRAF–MEK inhibition rarely results in solid tumours sustained disease control. Resistance is almost inevitable, NCT03979651, phase 1/2, completed as single genetic or signalling alterations can bypass Trametinib MEK inhibition NRASmut melanoma combination pathway inhibition.96 Moreover, MEK Hydroxychloroquine Autophagy inhibition NRASmut melanoma inhibitor sensitivity is shaped by adaptive signalling, (Table 3 continues on next page) tumour microenvironmental cues, and epigenetic repro- gramming, all of which contribute to treatment failure. 1648 Therapeutics MAPK pathway reactivation in the presence of BRAF Drug action Study focus inhibitors, MEK inhibitors, or both, frequently arises through alterations that directly aect drug targets, such as (Continued from previous page) BRAF amplification or mutations in MEK1 and MEK2.98,186–189 NCT04109456, phase 1, active, not recruiting Notably, resistance to dabrafenib and trametinib in patients Cobimetinib MEK inhibition Metastatic melanoma with melanoma occurs predomi nantly through mutations IN10018 (FAK) FAK inhibition Metastatic melanoma in MEK2 rather than MEK1,20 potentially reflecting ERK- NCT04201457, phase 1/2, active, not recruiting mediated inhibition of MEK1 through phosphorylation at Dabrafenib BRAF inhibition Recurrent low-grade or high-grade glioma with BRAF alteration the MEK1-specific regulatory residue Thr292 (figure 2). Trametinib MEK inhibition Recurrent low-grade or high-grade Phosphorylated MEK proteins also show reduced anity glioma with BRAF alteration for trametinib, diminishing drug ecacy.190 Hydroxychloroquine Autophagy inhibition Recurrent low-grade or high-grade Upstream events, including RAS mutations and glioma with BRAF alteration upregulation of RTKs such as EGFR and HER2, can NCT05585320, phase 1/2, active, not recruiting co-activate MAPK and compensatory PI3K–AKT Atebimetinib (IMM-1-104) MEK inhibition Metastatic pancreatic ductal signalling, enabling tumour cells to bypass BRAF and adenocarcinoma MEK inhibition.191,192 Activation of PI3K–AKT signalling Modified gemcitabine and nab- Inhibition of DNA synthesis and Metastatic pancreatic ductal can also occur via oncogenic mutations in PIK3CA, paclitaxel microtubule function adenocarcinoma AKT1, or AKT3, or via loss of the tumour suppressor Dabrafenib BRAF inhibition BRAFmut melanoma post anti-PD- (L)1 monoclonal antibody PTEN.193,194 In gastric cancer, for instance, MEK blockade progression induces rebound activation of KRASWT and the SHP2 phosphatase, promoting RTK-dependent signalling and NSCLC=non-small-cell lung cancer. resistance.195 MEK inhibition relieves ERK-mediated Table 3: Interventions in clinical trials involving MEK inhibitor combination therapies negative feedback on RTKs, such as EGFR and HER2, thereby enhancing ERBB3-driven PI3K–AKT signalling and contributing to resistance.196 Toxicity In colorectal cancer, MEK inhibition persistently reduced Dosing of MEK inhibitors is limited by their toxicity AXIN1 protein concentrations and disrupted its interaction profiles, with adverse eects occurring in the majority of with GSK3B, leading to activation of Wnt, stem-cell treated patients and aecting multiple organ systems. plasticity, and therapy resistance.197 Similarly, MEK These toxic eects range from mild to severe.202 inhibition can activate STAT3 via FGFR and JAK kinases, Dermatological toxic eects are the most frequent and are creating a positive feedback loop that sustains survival often dose-limiting. Rashes, such as acneiform dermatitis signalling in drug-treated, oncogene-addicted cancer and maculopapular eruptions, aect a large proportion of cells.198 patients and substantially aect their quality of life.203,204 These mechanistic insights suggest rational avenues Gastrointestinal adverse eects, including diarrhoea, for combination therapies aimed at delaying or over- nausea, and vomiting, are the second most common and coming MEK inhibitor resistance. Cotargeting MEK and aect more than 20% of patients treated with MEK RTKs (eg, EGFR, HER2, or ERBB3) or inhibiting parallel inhibitors.202,203 Ocular toxic eects are uniquely associated survival pathways, including PI3K–AKT or Wnt with MEK inhibitors and include central serous signalling, has shown promise in preclinical models. retinopathy and retinal vein occlusion.203 Whereas serous Dual inhibition strategies, such as combining MEK with retinopathy typically resolves with treatment interruption, SHP2 or PI3K inhibitors,199 are being explored to suppress retinal vein occlusion can result in irreversible vision adaptive feedback loops and restore drug sensitivity. loss.204 Cardiotoxicity, such as reduced ejection fraction or These findings underscore the potential of context- ventricular dysfunction, has been reported in up to 7% of specific, mechanism-driven combinations to improve the patients, and interstitial lung disease or pneumonitis, durability of MAPK pathway inhibition across diverse although less frequent, can be fatal.203,204 Other common tumour types. toxic eects include fatigue and peripheral oedema, which The tumour microenvironment can also contribute to compound treatment burden.205 MEK inhibitor resistance. HGF and FGF secreted by These toxic eects not only impair quality of life but also stromal cells (eg, fibroblasts) in the tumour micro- limit dose intensity and duration of therapy. Among MEK environment can reactivate MAPK signalling or stimulate inhibitors, induced grade 3–4 events or death were higher alternative survival pathways. For example, HGF binding among patients prescribed binimetinib (69% [95% CI to its receptor MET activates the PI3K–AKT pathway and 50–84]) than for patients prescribed trametinib (36% promotes cell survival, despite MEK suppression.200 [17–60]).202 To improve tolerability while preserving Longitudinal studies on trametinib-treated murine ecacy, several strategies have been explored, including melanoma have shown intratumoural reorganisation alternative dosing schedules, dose reductions, and lower- involving bundled collagen deposition, which might dose combination regimens.206 In a phase 2 trial of promote resistance to targeted therapy over time.201 trametinib for BRAFV⁶⁰⁰ and NRASQ⁶¹ wild-type immune Therapeutics checkpoint inhibitor-refractory melanoma, the inhibitors.212,213 Mechanistically novel compounds, combination of trametinib with low-dose dabrafenib including allosteric variants with alternative binding (50 mg twice daily) mitigated treatment-limiting skin modes, and dual inhibitors that simultaneously target toxicity while maintaining clinical activity, with a 29% MEK and upstream or downstream MAPK eectors, ORR (seven of 24 patients) and disease control in nine could overcome resistance and expand the therapeutic (64%) of 14 patients with MAPK pathway-activating window. alterations.207 Combination therapy remains a cornerstone of MEK inhibitor development. Dual MAPK pathway inhibition, Future directions and perspectives exemplified by BRAF and MEK inhibitor combinations, MEK inhibitors have emerged as key agents in the has improved survival in patients with melanoma and treatment of BRAF-driven and RAS-driven malignancies. patients with other cancers. This paradigm is evolving However, their broader clinical eect has been limited by toward triplet regimens incorporating immune adaptive resistance, dose-limiting toxic eects, and poor checkpoint inhibitors, PI3K–mTOR pathway agents, or durability of response when used as monotherapy. To proapoptotic drugs. Rational combinations tailored to fully realise the therapeutic potential of MEK pathway tumour-specific vulnerabilities guided by genomic and inhibition, several crucial avenues of research must be functional profiling are likely to define the next pursued. generation of MEK-based therapies. Many current- Refining patient selection through predictive generation MEK inhibitor-based combinations, including biomarkers is essential. Although activating mutations in those with immune checkpoint inhibitors, PI3K–mTOR RAS and RAF are often associated with MEK inhibitor inhibitors, or pan-RAF inhibitors, have shown little sensitivity, clinical outcomes remain heterogenous and activity or unacceptable toxicity. To overcome these variable. In the COMBI-AD trial, patients with low challenges, strategies under investigation include lower- tumour mutational burden derived greatest benefit from dose or intermittent scheduling, sequential rather than combination therapy, while those with high tumour concurrent administration, and alternative tumour- mutational burden and low type II interferon signatures directed delivery strategies, such as nanoparticles, showed little response.208 Additionally, patients with liposomes, or RNA-based therapeutics,214 which aim to BRAFV⁶⁰⁰K mutations did not have the same overall improve ecacy and reduce systemic toxicity. survival benefit as those with BRAFV⁶⁰⁰E mutations, which Although oncology remains the primary focus, aberrant highlights the need to account for mutational subtype MAPK signalling has been implicated in fibrotic, when considering treatment strategies.209 Whole-exome inflammatory, and developmental diseases. Preclinical and RNA sequencing analyses of patients who had a data suggest potential applications of MEK inhibition response versus those who did not showed higher rates of beyond cancer, although early-phase clinical evidence is MITF amplification and TP53 mutation in non- scarce. Translational studies are needed to evaluate safety, responding tumours, whereas NF1 deletion was more ecacy, and therapeutic windows in non-malignant common in responding tumours, and transcriptional contexts. signatures of CD8 T eector cells, antigen presentation, The future of MEK inhibitors lies not in monotherapy, and natural killer cells were enriched in responders.210 but in the integration of MEK inhibitors into biomarker- Emerging tools, such as comprehensive genomic driven, combination-based, and precision-guided profiling, circulating tumour DNA, and functional assays strategies. With ongoing innovations in drug design and of MAPK pathway activity oer promise for identifying a deepening understanding of resistance biology, MEK responsive subgroups and detecting early resistance. inhibition is poised to remain a foundational element of Integrating somatic and germline alterations, targeted therapy and potentially extend its relevance transcriptional signatures, and pathway activity metrics beyond oncology. will be central to identifying durable responders. Contributors Refinements in drug design are expected to improve WYC, IPdS, and HR drafted the initial version of the manuscript. All both ecacy and tolerability. Next-generation MEK authors contributed to data analysis and interpretation, critically reviewed and edited subsequent drafts, and approved the final version inhibitors with enhanced potency and selectivity, for submission. reduced toxicity, and alternative formulations (eg, topical Declaration of interests or targeted delivery) are in early development.211 GVL is a consultant advisor for Agenus, AstraZeneca UK, Bayer Tunlametinib (HL-085) has shown higher inhibitory HealthCare Pharmaceuticals, BioNTech, Boehringer Ingelheim activity than some earlier MEK inhibitors in preclinical International, Bristol Myers Squibb, Byondis, Evaxion Biotech, Fortiva studies (with significantly lower half maximal inhibitory Biologics USA, GI Innovation, Hexal (a Sandoz Company), Highlight Therapeutics, Immunocore Ireland, Innovent Biologics USA, IOBiotech, concentration values and strong suppression of ERK Iovance Biotherapeutics, Merck Sharp & Dohme, Novartis Pharma, signalling) and encouraging clinical activity in NRASmut Pierre Fabre, Regeneron Pharmaceuticals, Scancell, SkylineDX, and melanoma (ORR 35·8% [95% CI 26·2–46·3]), which Strand Therapeutics. IPdS reports travel support from Bristol Myers has led to regulatory approval in China and ongoing Squibb and Merck Sharp & Dohme; reports speakers fees from Pierre Fabre, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, and clinical evaluation of combinations with BRAF 1650 Therapeutics Novartis; and has served as a consultant on advisory boards from Merck 19 Takekawa M, Tatebayashi K, Saito H. Conserved docking site is Sharp & Dohme, Regeneron, and Strand. WYC reports a speakers fee essential for activation of mammalian MAP kinase kinases by from AstraZeneca UK, and is supported by the CLEARbridge specific MAP kinase kinase kinases. Mol Cell 2005; 18: 295–306. Foundation, a Melanoma Institute Australia PhD scholarship, and a Tour 20 Long GV, Fung C, Menzies AM, et al. Increased MAPK de Cure Postgraduate Research Grant. HR declares no competing reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. interests. Nat Commun 2014; 5: 5694. Acknowledgments 21 Rizos H, Menzies AM, Pupo GM, et al. BRAF inhibitor resistance WYC is supported by the CLEARbridge Foundation, a Melanoma mechanisms in metastatic melanoma: spectrum and clinical Institute Australia PhD scholarship, and a Tour de Cure Postgraduate impact. Clin Cancer Res 2014; 20: 1965–77. Research Grant. GVL is supported by the Australian National Health and 22 Johnson DB, Menzies AM, Zimmer L, et al. Acquired BRAF Medical Research Council (NHMRC) Investigator Grant inhibitor resistance: a multicenter meta-analysis of the spectrum (2021/GNT2007839) and by the University of Sydney Medical and frequencies, clinical behaviour, and phenotypic associations of Foundation. IPS is supported by an NHMRC Investigator resistance mechanisms. Eur J Cancer 2015; 51: 2792–99. Grant (2024/GNT2033412) and the Melanoma Research Alliance Young 23 Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics Investigator Award. 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Biomater Adv 2023; 154: 213643. combination trials. Cancer Treat Rev 2021; 92: 102137. Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an 212 Liu Y, Cheng Y, Huang G, Xia X, Wang X, Tian H. Preclinical characterization of tunlametinib, a novel, potent, and selective MEK Open Access article under the CC BY 4.0 license. inhibitor. Front Pharmacol 2023; 14: 1271268. 1656 --- [PDF原文](https://sci-net.xyz/storage/7932541/8c019d1359d38bf7c0227ddc6b61c4b83461ed5a9f1884765b23e8a4bb13c242/Targeting-MEK-in-cancer-and-beyond-mechanistic-insights-and-therapeutic-opportunities.pdf) DOI: 10.1016/S0140-6736(26)00199-6