Journal
CELL REPORTS
Volume 8, Issue 4, Pages 1037-1048Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.07.010
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Funding
- Prostate Cancer Foundation (PCF)
- Samuel Waxman Cancer Research Foundation [CA-0052023]
- NIH (CHLA) [479/Prime: P01 CA081403]
- Stand Up to Cancer - Prostate Cancer Foundation - Prostate Dream Team Translational Cancer Research Grant
- Movember Foundation
- Biomedical Technology Research Centers program of the NIH National Institute of General Medical Sciences, NIH NIGMS [8P41GM103481]
- University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research (CFAR), an NIH [P30 AI027763]
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Despite the development of potent RAF/mitogen-activated protein kinase (MAPK) pathway inhibitors, only a fraction of BRAF-mutant patients benefit from treatment with these drugs. Using a combined chemogenomics and chemoproteomics approach, we identify drug-induced RAS-RAF-MEK complex formation in a subset of BRAF-mutant cancer cells characterized by primary resistance to vemurafenib. In these cells, autocrine interleukin-6 (IL-6) secretion may contribute to the primary resistance phenotype via induction of JAK/STAT3 and MAPK signaling. In a subset of cell lines, combined IL-6/MAPK inhibition is able to overcome primary resistance to BRAF-targeted therapy. Overall, we show that the signaling plasticity exerted by primary resistant BRAF-mutant cells is achieved by their ability to mimic signaling features of oncogenic RAS, a strategy that we term oncogene mimicry.'' This model may guide future strategies for overcoming primary resistance observed in these tumors.
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