trametinib

Overview

Allosteric MEK1/2 inhibitor.

Evidence in the corpus

  • Used as matched targeted therapy for MAP2K1-mutant histiocytosis patients in the Make-an-IMPACT program; MEK inhibition (trametinib/cobimetinib) contributed to clinical benefit in 17/18 treated histiocytosis patients (mean duration 21.7 months, range 6–40+) PMID:36862133.
  • A PTPN11-mutant histiocytosis patient and an NRAS-mutant case were also treated with MEK inhibitor PMID:36862133.
  • Trametinib (MEK inhibitor monotherapy) provided durable benefit in pilocytic astrocytoma patients with BRAF fusions (median 11 months, all 6 patients >6 months on therapy); combination with BRAF inhibitors was less durable (median 1 month) in a tumor-agnostic BRAF fusion cohort (N=241) PMID:38922339.
  • One patient with acquired BRAF fusion after EGFR TKI resistance remained on erlotinib + trametinib for 12 months PMID:38922339.
  • RMS PDTOs from the UCLA sarcoma screen were significantly more sensitive to trametinib than the pan-sarcoma average (p=0.013), providing functional evidence of MEK dependency in rhabdomyosarcoma independent of specific genomic driver identification. PMID:39305899
  • Referenced as a MAPK pathway inhibitor in the context of resistance to combined KRASG12C + EGFR inhibition in colorectal cancer; MEK1 (MAP2K1) mutations emerged as resistance alterations in patients treated with sotorasib or adagrasib plus anti-EGFR therapy PMID:36355783
  • MAP2K2 mutations (C125S, N126D, V35M, L46F) identified in BRAF V600 melanoma patients on RAF inhibitors conferred 3–20-fold trametinib resistance in A375 cells; MITF overexpression also produced pan-RAF/MEK/ERK cross-resistance PMID:24265153
  • Combined dabrafenib + trametinib (BRAF + MEK inhibition) selectively killed BRAF-mutant (K601N) MM cells in vitro without benefit in BRAF-WT, KRAS-G12A or NRAS-G12D cells, supporting the combination for clonally BRAF-mutant MM PMID:24434212
  • Authors of a 147-sample RMS landscape study cite trametinib (MEK1/2 inhibitor) as a rational effector-pathway strategy for the RAS-axis-altered subset (~45% of PAX-fusion-negative RMS) given its established efficacy in NRAS-mutant melanoma and preclinical RMS evidence PMID:24436047
  • BRAF V600E-mutant CCA (3–7% iCCA, near 0% eCCA): ROAR basket phase II ORR ~47% in 43 CCA patients, mPFS ~9 mo, mOS ~14 mo in combination with dabrafenib PMID:25526346
  • One of three FDA-approved BRAF-targeted therapies for the BRAF-mutant melanoma subtype (52% of 318 TCGA cases); also nominated for NF1-mutant subtype (14% of cases) to extend MEK inhibition to BRAF-wildtype patients in TCGA melanoma analysis PMID:26091043
  • Referenced as prior MAPKi context in Hugo et al. anti-PD-1 melanoma study (n=38): 14/38 patients had prior MAPK-inhibitor therapy including vemurafenib, dabrafenib, or trametinib; MAPKi treatment induces transcriptional programs overlapping the IPRES innate anti-PD-1 resistance signature, implicating prior trametinib therapy as a potential driver of cross-resistance to subsequent anti-PD-1 in BRAF- or NF1-mutant melanoma PMID:26997480
  • MEK inhibitor; proposed as therapeutic candidate for KRAS/NRAS/GNAQ-altered cisplatin-resistant GCT (KRAS in 22/180, NRAS in 4/180, GNAQ Q209P in 1/180) per Appendix Table A2 PMID:27646943

Resistance mechanisms

  • Not reported in corpus.

Cancer types (linked)

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36355783

This page was processed by crosslinker on 2026-05-14. - PMID:24265153

This page was processed by crosslinker on 2026-05-14. - PMID:24434212

This page was processed by crosslinker on 2026-05-14. - PMID:24436047

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14. - PMID:26091043 - PMID:26997480

This page was processed by entity-page-writer on 2026-05-15. - PMID:27646943

This page was processed by wiki-cli on 2026-05-14.