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

作者：Villanueva Jessie; Vultur Adina; Lee John T; Somasundaram Rajasekharan; Fukunaga Kalabis Mizuho; Cipolla Angela K; Wubbenhorst Bradley; Xu Xiaowei; Gimotty Phyllis A; Kee Damien; Santiago Walker Ademi E; Letrero Richard; D'; Andrea Kurt; Pushparajan Anitha; Hayden James E; Brown Kimberly Dahlman; Laquerre Sylvie; McArthur Grant A; Sosman Jeffrey A; Nathanson Katherine L; Herlyn Meenhard^*

来源：Cancer Cell, 2010, 18(6): 683-695.

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(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.

• 出版日期2010-12-14