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Cell Rep. 2014 Aug 21;8(4):1037-48. doi: 10.1016/j.celrep.2014.07.010. Epub 2014 Aug 7.

Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors.

Author information

1
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, CA 94158, USA.
3
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, CA 94158, USA.
5
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: kevan.shokat@ucsf.edu.

Abstract

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.

PMID:
25127139
PMCID:
PMC4294625
DOI:
10.1016/j.celrep.2014.07.010
[Indexed for MEDLINE]
Free PMC Article

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