Reference Detail

Ref Type

Journal Article

PMID

(24265153)

Authors

Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D

Title

The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	4	1	2014 Jan	94-109	Cancer Discov

URL

Abstract Text

Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a "long tail" of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
VX-11e	VX-11e	6	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
VX-11e		VX11e\|VX 11e\|VTX-11e\|VRT-11E\|VRT11E	ERK Inhibitor (pan) 21	VX-11e is an ATP-competitive inhibitor of Mapk1 (Erk2) and Mapk3 (Erk1), which may result in growth inhibition and tumor regression (PMID: 19827834, PMID: 24265153, PMID: 31935908).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
MAP2K1	G128V	missense	unknown	MAP2K1 G128V lies within the protein kinase domain of the Map2k1 protein (UniProt.org). G128V results in autophosphorylation levels similar to wild-type Map2k1 in an in vitro assay (PMID: 29753091) and has been described as a drug resistance mutation (PMID: 24265153), but leads to increased Erk phosphorylation, enhanced cell cycle progression, increased colony formation, and elevated autophagy induction compared to wild-type Map2k1 in culture (PMID: 31972311), and therefore, its effect on Map2k1 protein function is unknown.	Y
MAP2K1	V60E	missense	gain of function	MAP2K1 V60E does not lie within any known functional domains of the Map2k1 protein (UniProt.org). V60E confers a gain of function to Map2k1 as demonstrated by increased Erk signaling (PMID: 28263969), transformation activity in cultured cells and increased proliferation in a competition assay (PMID: 36442478), and tumor formation in orthotopic mouse models (PMID: 28263969), and demonstrates resistance to some Braf inhibitors (PMID: 24265153, PMID: 28263969, PMID: 36442478).	Y
TSC2	P1770S	missense	unknown	TSC2 P1770S does not lie within any known functional domains of the Tsc2 protein (UniProt.org). P1770S has been identified in sequencing studies (PMID: 24265153), but has not been biochemically characterized and therefore, its effect on Tsc2 protein function is unknown (PubMed, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E MAP2K1 P124L	melanoma	predicted - resistant	Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, Zelboraf (vemurafenib) treatment resulted in disease progression within 6 weeks in a metastatic melanoma patient harboring BRAF V600E and MAP2K1 P124L (PMID: 24265153).	24265153
BRAF V600E MAP2K1 G128V	melanoma	resistant	Trametinib	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 G128V demonstrated resistance to treatment with Mekinist (trametinib) in culture, resulting in sustained Map2k1/2 and Erk1/2 phosphorylation (PMID: 24265153).	24265153
BRAF V600E MAP2K1 G128V	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 G128V demonstrated resistance to treatment with Tafinlar (dabrafenib) in culture, resulting in sustained Map2k1/2 and Erk1/2 phosphorylation (PMID: 24265153).	24265153
MAP2K1 V60E	melanoma	resistant	Trametinib	Preclinical	Actionable	In a preclinical study, a melanoma cell line expressing MAP2K1 V60E demonstrated resistance to Mekinist (trametinib) in culture (PMID: 24265153).	24265153
BRAF V600X BRAF amp NRAS Q61K	melanoma	resistant	Vemurafenib	Clinical Study - Cohort	Actionable	In a clinical study, a melanoma patient harboring a BRAF V600 mutation developed resistant mutations, BRAF amplification and NRAS Q61K, during treatment with Zelboraf (vemurafenib) (PMID: 24265153).	24265153
BRAF V600E MAP2K1 V60E	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 V60E demonstrated resistance to treatment with Tafinlar (dabrafenib) in culture, resulting in sustained Map2k1/2 and Erk1/2 phosphorylation (PMID: 24265153).	24265153
BRAF V600E MAP2K1 P124S	melanoma	resistant	Trametinib	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124S demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 24265153).	24265153
BRAF V600E MAP2K1 V60E	melanoma	sensitive	VX-11e	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 V60E demonstrated sensitivity to treatment with VX-11e, resulting in decreased cell growth in culture (PMID: 24265153).	24265153
BRAF V600E MAP2K1 G128V	melanoma	sensitive	VX-11e	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 G128V demonstrated sensitivity to treatment with VX-11e, resulting in decreased cell growth in culture (PMID: 24265153).	24265153
BRAF V600X MAP2K1 V60E NRAS T58I NRAS Q61R	melanoma	predicted - resistant	Vemurafenib	Clinical Study - Cohort	Actionable	In a clinical study, a melanoma patient harboring a BRAF V600 mutation developed resistance-associated mutations, MAP2K1 V60E, NRAS T58I, and NRAS Q61R, after 18 weeks of treatment with Zelboraf (vemurafenib) (PMID: 24265153).	24265153
BRAF V600K MAP2K1 P124S	melanoma	predicted - resistant	Dabrafenib	Case Reports/Case Series	Actionable	In a clinical case study, Tafinlar (dabrafenib) treatment resulted in disease progression within 5 weeks in a metastatic melanoma patient harboring BRAF V600K and MAP2K1 P124S (PMID: 24265153).	24265153
BRAF V600X PTEN H93D	melanoma	predicted - sensitive	Vemurafenib	Clinical Study - Cohort	Actionable	In a clinical study, a melanoma patient harboring a BRAF V600 mutation and PTEN H93D treated with Zelboraf (vemurafenib) for 66 weeks demonstrated a partial response (PMID: 24265153).	24265153
MAP2K1 V60E	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, a melanoma cell line expressing MAP2K1 V60E demonstrated resistance to Tafinlar (dabrafenib) in culture (PMID: 24265153).	24265153
BRAF V600E MAP2K1 P124S	melanoma	sensitive	VX-11e	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124S demonstrated sensitivity to treatment with VX-11e, resulting in decreased cell growth in culture (PMID: 24265153).	24265153
BRAF V600E PTEN loss	melanoma	sensitive	Pictilisib + PLX4720	Preclinical	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600E and PTEN loss demonstrated sensitivity when treated with a combination of Pictilisib (GDC-0941) and PLX4720, resulting in decreased cell proliferation in culture (PMID: 24265153).	24265153
BRAF V600E MAP2K1 C121S	melanoma	sensitive	VX-11e	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 C121S demonstrated sensitivity to treatment with VX-11e, resulting in decreased cell growth in culture (PMID: 24265153).	24265153
BRAF V600E MAP2K1 P124S	melanoma	resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124S demonstrated resistance to treatment with Tafinlar (dabrafenib) in culture (PMID: 24265153).	24265153
BRAF V600E PIK3CA H1047R PTEN Y68fs	melanoma	predicted - resistant	Vemurafenib	Case Reports/Case Series	Actionable	In a clinical study, a melanoma patient harboring BRAF V600E and PTEN Y68fs treated with Zelboraf (vemurafenib) was found to have acquired PIK3CA H1047R in the post-progression tumor biopsy (PMID: 24265153).	24265153