Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm
  • Indoles
  • MAP Kinase Kinase 1
  • Melanoma
  • Mutation
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Skin Neoplasms
  • Sulfonamides

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.

publication date

  • August 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3157968

Digital Object Identifier (DOI)

  • 10.1200/JCO.2010.33.2312

PubMed ID

  • 21383288

Additional Document Info

start page

  • 3085

end page

  • 96

volume

  • 29

number

  • 22