Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors

Martin L Sos; Rebecca S Levin; John D Gordan; Juan A Oses-Prieto; James T Webber; Megan Salt; Byron Hann; Alma L Burlingame; Frank McCormick; Sourav Bandyopadhyay; Kevan M Shokat

doi:10.1016/j.celrep.2014.07.010

Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis
Autocrine Communication
Benzamides / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Diphenylamine / analogs & derivatives*
Diphenylamine / pharmacology
Drug Resistance, Neoplasm / genetics*
Female
Humans
Interleukin-6 / metabolism
MAP Kinase Signaling System
Mice, Nude
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / metabolism
Mutation, Missense
Niacinamide / analogs & derivatives*
Niacinamide / pharmacology
Oncogenes*
Phenylurea Compounds / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics
Sorafenib
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Benzamides
IL6 protein, human
Interleukin-6
Phenylurea Compounds
Niacinamide
mirdametinib
Diphenylamine
Sorafenib
BRAF protein, human
Proto-Oncogene Proteins B-raf
Mitogen-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding