Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

Cancer Cell. 2010 Dec 14;18(6):683-95. doi: 10.1016/j.ccr.2010.11.023.

Abstract

BRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAF(V)⁶⁰⁰(E) melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • MAP Kinase Signaling System
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / physiology
  • raf Kinases / physiology*

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • raf Kinases
  • Mitogen-Activated Protein Kinase Kinases