Journal
CANCER CELL
Volume 18, Issue 6, Pages 683-695Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2010.11.023
Keywords
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Categories
Funding
- National Cancer Institute [P01 CA114046, P01 CA025874, P30 CA010815, RO1 CA117881]
- Adelson Medical Research Foundation
- GlaxoSmithKline
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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(V600E) 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.
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