Reference Detail

Ref Type

Journal Article

PMID

(21383288)

Authors

Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, Hahn WC, Meyerson M, Garraway LA

Title

Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of	29	22	2011 Aug 1	3085-96	J Clin Oncol

URL

Abstract Text

A detailed understanding of the mechanisms by which tumors acquire resistance to targeted anticancer agents should speed the development of treatment strategies with lasting clinical efficacy. RAF inhibition in BRAF-mutant melanoma exemplifies the promise and challenge of many targeted drugs; although response rates are high, resistance invariably develops. Here, we articulate overarching principles of resistance to kinase inhibitors, as well as a translational approach to characterize resistance in the clinical setting through tumor mutation profiling. As a proof of principle, we performed targeted, massively parallel sequencing of 138 cancer genes in a tumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response. The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the corresponding pretreatment tumor. The MEK1(C121S) mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Thus, MEK1(C121S) or functionally similar mutations are predicted to confer resistance to combined MEK/RAF inhibition. These results provide an instructive framework for assessing mechanisms of acquired resistance to kinase inhibition and illustrate the use of emerging technologies in a manner that may accelerate personalized cancer medicine.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
MAP2K1	C121S	missense	gain of function	MAP2K1 C121S lies within the protein kinase domain of the Map2k1 protein (UniProt.org). C121S confers a gain of function on the Map2k1 protein as demonstrated by increased Erk1/2 (PMID: 25899310) and Mek phosphorylation in culture and confers acquired resistance to Raf and Mek inhibitors (PMID: 21383288, PMID: 24448821, PMID: 29483135, PMID: 29753091).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E MAP2K1 C121S	melanoma	resistant	Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient harboring BRAF V600E demonstrated an initial response to treatment with Zelboraf (vemurafenib), but progressed following emergence of a MAP2K1 C121S mutation (PMID: 21383288).	21383288
BRAF V600E MAP2K1 C121S	melanoma	resistant	PLX4720	Preclinical	Actionable	In a preclinical study, expression of MAP2K1 C121S conferred resistance to PLX4720 in melanoma cells harboring BRAF V600E in culture (PMID: 21383288).	21383288