Author/Authors :
Villanueva، نويسنده , , Jessie and Vultur، نويسنده , , Adina and Lee، نويسنده , , John T. and Somasundaram، نويسنده , , Rajasekharan and Fukunaga-Kalabis، نويسنده , , Mizuho and Cipolla، نويسنده , , Angela K. and Wubbenhorst، نويسنده , , Bradley and Xu، نويسنده , , Xiaowei and Gimotty، نويسنده , , Phyllis A. and Kee، نويسنده , , Damien and Santiago-Walker، نويسنده , , Ademi E. and Letrero، نويسنده , , Richard and DʹAndrea، نويسنده , , Kurt and Pushparajan، نويسنده , , Anitha and Hayden، نويسنده , , James E. and Brown، نويسنده , , Kimberly Dahlman and Laquerre، نويسنده , , Sylvie and McArthur، نويسنده , , Grant A. and Sosman، نويسنده , , Jeffrey A. and Nathanson، نويسنده , , Katherine L. and Herlyn، نويسنده , , Meenhard، نويسنده ,
Abstract :
Summary
s 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.
