Cancer Cell
Volume 18, Issue 6, 14 December 2010, Pages 683-695
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Article
Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

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Summary

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 BRAFV600E 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.

Highlights

► Chronic BRAF inhibition in BRAFV600E melanoma cells leads to drug resistance ► BRAF inhibitor resistant cells switch among the three RAF isoforms to activate MAPK ► IGF1R/PI3K signaling promotes survival of BRAF-inhibitor resistant cells ► Coinhibition of MEK and IGF1R/PI3K leads to cytotoxicity in resistant melanoma cells

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