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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 Cancer discovery
Vol 4
Issue 1
Date 2014 Jan
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
VRT11E VRT11E 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
VRT11E VRT-11E ERK Inhibitor (pan) 15 VRT11E is an inhibitor of Erk, which may result in decreased cell growth (PMID: 24265153, PMID: 31935908).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ARID1A Q1334del deletion unknown ARID1A Q1334del results in the deletion of one amino acid in the Arid1a protein at amino acid 1334 (UniProt.org). Q1334del has been identified in the scientific literature (PMID: 23097632, PMID: 24265153), but has not been biochemically characterized and therefore, its effect on Arid1a protein function is unknown (PubMed, Jul 2020).
ETV6 R259Q missense unknown ETV6 R259Q lies within the linker domain of the Etv6 protein (PMID: 25581430). R259Q has been identified in sequencing studies (PMID: 29057546, PMID: 22895193, PMID: 24265153), but has not been biochemically characterized and therefore, its effect on Etv6 protein function is unknown (PubMed, Apr 2020).
FANCA R1011H missense unknown FANCA R1011H does not lie within any known functional domains of the Fanca protein (UniProt.org). R1011H has been identified in sequencing studies (PMID: 24265153), but has not been biochemically characterized and therefore, its effect on Fanca protein function is unknown (PubMed, Jul 2020).
FANCA S734F missense unknown FANCA S734F does not lie within any known functional domains of the Fanca protein (UniProt.org). S734F has been identified in sequencing studies (PMID: 24265153), but has not been biochemically characterized and therefore, its effect on Fanca protein function is unknown (PubMed, Jul 2020).
FGFR2 E695K missense unknown FGFR2 E695K lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). E695K has been identified in sequencing studies (PMID: 24265153, PMID: 28481359), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, May 2020).
GATA2 P228L missense unknown GATA2 P228L does not lie within any known functional domains of the Gata2 protein (UniProt.org). P228L has been identified in sequencing studies (PMID: 24265153), but has not been biochemically characterized and therefore, its effect on Gata2 protein function is unknown (PubMed, May 2020).
KDR R787W missense unknown KDR (VEGFR2) R787W lies within the cytoplasmic domain of the Kdr (Vegfr2) protein (UniProt.org). R787W has been identified in sequencing studies (PMID: 24265153, PMID: 30239046), but has not been biochemically characterized and therefore, its effect on Kdr (Vegfr2) protein function is unknown (PubMed, Jul 2020).
MAP2K1 G128V missense unknown MAP2K1 G128V lies within the protein kinase domain of the Map2k1 protein (UniProt.org). G128V has been demonstrated to have autophosphorylation levels similar to wild-type Map2k1 in an in vitro assay (PMID: 29753091) and has also been described as a drug resistance mutation (PMID: 24265153), but has shown 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 results in increased Erk signaling in cultured cells and tumor formation in orthotopic mouse models (PMID: 28263969), and has been described as a drug resistance mutation (PMID: 24265153, PMID: 28263969). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 sensitive VRT11E Preclinical Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 G128V demonstrated sensitivity to treatment with VRT11E, resulting in decreased cell growth in culture (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 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 MAP2K1 P124S melanoma sensitive VRT11E Preclinical Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124S demonstrated sensitivity to treatment with VRT11E, resulting in decreased cell growth 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 sensitive VRT11E Preclinical Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 V60E demonstrated sensitivity to treatment with VRT11E, 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 V600E MAP2K1 C121S melanoma sensitive VRT11E Preclinical Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 C121S demonstrated sensitivity to treatment with VRT11E, resulting in decreased cell growth in culture (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 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