Journal article
Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K
J Villanueva, A Vultur, JT Lee, R Somasundaram, M Fukunaga-Kalabis, AK Cipolla, B Wubbenhorst, X Xu, PA Gimotty, D Kee, AE Santiago-Walker, R Letrero, K D'Andrea, A Pushparajan, JE Hayden, KD Brown, S Laquerre, GA McArthur, JA Sosman, KL Nathanson Show all
Cancer Cell | Published : 2010
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 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 leve..
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Awarded by National Cancer Institute
Funding Acknowledgements
We thank T. Nguyen and F. Keeney for assistance with graphics, T. Wang for help with Annexin-V analysis, and J. Kong, Y, Chen, S. Huang, M. Neri, and S. Lee for technical assistance. We thank the Microscopy and Flow Cytometry facilities at the Wistar Institute and G. Bollag for providing PLX4720. We apologize to those whose work is not mentioned here due to space constraints. This work was supported by grants from the National Cancer Institute (P01 CA114046, P01 CA025874, P30 CA010815, RO1 CA117881), the Adelson Medical Research Foundation, and GlaxoSmithKline. Sylvie Laquerre is an employee and shareholder of GlaxoSmithKline.