You are here

J Clin Oncol DOI:10.1200/JCO.2010.33.2312

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

Publication TypeJournal Article
Year of Publication2011
AuthorsWagle, N, Emery, C, Berger, MF, Davis, MJ, Sawyer, A, Pochanard, P, Kehoe, SM, Johannessen, CM, MacConaill, LE, Hahn, WC, Meyerson, M, Garraway, LA
JournalJ Clin Oncol
Date Published2011 Aug 01
KeywordsAdult, Antineoplastic Agents, Disease Progression, DNA Mutational Analysis, Drug Resistance, Neoplasm, Fatal Outcome, Gene Expression Profiling, Humans, Indoles, Male, MAP Kinase Kinase 1, Melanoma, Mutation, Phosphatidylethanolamine Binding Protein, Precision Medicine, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Skin Neoplasms, Sulfonamides

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.


Alternate JournalJ. Clin. Oncol.
PubMed ID21383288
PubMed Central IDPMC3157968
Grant ListT32 CA009172 / CA / NCI NIH HHS / United States
DP2OD002750 / OD / NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
U24CA143867 / CA / NCI NIH HHS / United States
R33 CA126674 / CA / NCI NIH HHS / United States
R33CA126674 / CA / NCI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States