Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors

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...

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Main Authors:	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
Format:	Article
Language:	English
Published:	Elsevier 2014-08-01
Series:	Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211124714005774

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spelling	doaj-1a17ee8db0924b189b044aa9baf0a3392020-11-24T21:18:04ZengElsevierCell Reports2211-12472014-08-01841037104810.1016/j.celrep.2014.07.010Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF InhibitorsMartin L. Sos0Rebecca S. Levin1John D. Gordan2Juan A. Oses-Prieto3James T. Webber4Megan Salt5Byron Hann6Alma L. Burlingame7Frank McCormick8Sourav Bandyopadhyay9Kevan M. Shokat10Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USAHoward Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USAHoward Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USADepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, CA 94158, USADepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USADepartment of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USADepartment of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USADepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, CA 94158, USADepartment of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USADepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USAHoward Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USADespite 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.http://www.sciencedirect.com/science/article/pii/S2211124714005774
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	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
spellingShingle	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 Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors Cell Reports
author_facet	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
author_sort	Martin L. Sos
title	Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors
title_short	Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors
title_full	Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors
title_fullStr	Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors
title_full_unstemmed	Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors
title_sort	oncogene mimicry as a mechanism of primary resistance to braf inhibitors
publisher	Elsevier
series	Cell Reports
issn	2211-1247
publishDate	2014-08-01
description	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.
url	http://www.sciencedirect.com/science/article/pii/S2211124714005774
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Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors

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