Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K.

Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D'Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M
Cancer Cell. 2010 18 (6): 683-95

PMID: 21156289 · PMCID: PMC3026446 · DOI:10.1016/j.ccr.2010.11.023

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.

Copyright © 2010 Elsevier Inc. All rights reserved.

MeSH Terms (12)

Cell Line, Tumor Drug Resistance, Neoplasm Humans MAP Kinase Signaling System Melanoma Mitogen-Activated Protein Kinase Kinases Phosphatidylinositol 3-Kinases Phosphorylation Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-akt raf Kinases Receptor, IGF Type 1

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