Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K
Jessie Villanueva, Adina Vultur, John T Lee, Rajasekharan Somasundaram, Mizuho Fukunaga-Kalabis, Angela K Cipolla, Bradley Wubbenhorst, Xiaowei Xu, Phyllis A Gimotty, Damien Kee, Ademi E Santiago-Walker, Richard Letrero, Kurt D'Andrea, Anitha Pushparajan, James E Hayden, Kimberly Dahlman Brown, Sylvie Laquerre, Grant A McArthur, Jeffrey A Sosman, Katherine L Nathanson, Meenhard Herlyn, Jessie Villanueva, Adina Vultur, John T Lee, Rajasekharan Somasundaram, Mizuho Fukunaga-Kalabis, Angela K Cipolla, Bradley Wubbenhorst, Xiaowei Xu, Phyllis A Gimotty, Damien Kee, Ademi E Santiago-Walker, Richard Letrero, Kurt D'Andrea, Anitha Pushparajan, James E Hayden, Kimberly Dahlman Brown, Sylvie Laquerre, Grant A McArthur, Jeffrey A Sosman, Katherine L Nathanson, Meenhard Herlyn
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.
Copyright © 2010 Elsevier Inc. All rights reserved.
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Source: PubMed