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PMID: 21383288 Published · ppublish English Case Reports Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Journal of clinical oncology : official journal of the American Society of Clinical Oncology ·Vol. 29 ·No. 22 ·2011-08-01 ·Pages 3085-96

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

Abstract

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.

MeSH Terms
Adult Antineoplastic Agents/pharmacology,therapeutic use DNA Mutational Analysis Disease Progression Drug Resistance, Neoplasm/genetics Fatal Outcome Gene Expression Profiling Humans Indoles/pharmacology,therapeutic use MAP Kinase Kinase 1/genetics Male Melanoma/drug therapy,genetics,secondary Mutation Phosphatidylethanolamine Binding Protein/genetics Precision Medicine/methods Protein Kinase Inhibitors/pharmacology,therapeutic use Proto-Oncogene Proteins B-raf/genetics Skin Neoplasms/drug therapy,genetics,pathology Sulfonamides/pharmacology,therapeutic use Vemurafenib
Chemicals
Antineoplastic Agents Indoles PEBP1 protein, human Phosphatidylethanolamine Binding Protein Protein Kinase Inhibitors Sulfonamides Vemurafenib BRAF protein, human Proto-Oncogene Proteins B-raf MAP Kinase Kinase 1 MAP2K1 protein, human
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Wagle Nikhil
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, D1542, Boston, MA, USA.
Emery Caroline
Berger Michael F
Davis Matthew J
Sawyer Allison
Pochanard Panisa
Kehoe Sarah M
Johannessen Cory M
Macconaill Laura E
Hahn William C
Meyerson Matthew
Garraway Levi A
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Article Info
Journal
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Abbr.
J Clin Oncol
ISSN
1527-7755
DOI
10.1200/JCO.2010.33.2312
Published
2011-08-01
Epub
2011-00-07
Pages
3085-96
Language
English
Region
United States
NLM ID
8309333
PMCID
PMC3157968
Subset
IM
Grants
NCI NIH HHS · T32 CA009172 · United States
NCI NIH HHS · R33 CA126674 · United States
NCI NIH HHS · R33CA126674 · United States
NCI NIH HHS · U24 CA143867 · United States
NIH HHS · DP2OD002750 · United States
NIH HHS · DP2 OD002750 · United States
NCI NIH HHS · U24CA143867 · United States
External Links
PubMed source DOI: 10.1200/JCO.2010.33.2312 PMC Full Text View journal details
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