Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors.

Autor:	Merchant M; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Moffat J; Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California, United States of America., Schaefer G; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Chan J; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Wang X; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Orr C; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Cheng J; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Hunsaker T; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Shao L; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America., Wang SJ; Department of Biological Engineering, The Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America., Wagle MC; Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, United States of America., Lin E; Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, United States of America., Haverty PM; Department of Bioinformatics, Genentech, Inc., South San Francisco, California, United States of America., Shahidi-Latham S; Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, United States of America., Ngu H; Department of Pathology, Genentech, Inc., South San Francisco, California, United States of America., Solon M; Department of Discovery Chemistry, Genentech, Inc., South San Francisco, California, United States of America., Eastham-Anderson J; Department of Pathology, Genentech, Inc., South San Francisco, California, United States of America., Koeppen H; Department of Pathology, Genentech, Inc., South San Francisco, California, United States of America., Huang SA; Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, United States of America., Schwarz J; Department of Discovery Chemistry, Genentech, Inc., South San Francisco, California, United States of America., Belvin M; Department of Cancer Immunology, Genentech, Inc., South San Francisco, California, United States of America., Kirouac D; Department of Pre-clinical & Translational Pharmacokinetics Genentech, Inc., South San Francisco, California, United States of America., Junttila MR; Department of Translational Oncology, Genentech, Inc., South San Francisco, California, United States of America.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2017 Oct 05; Vol. 12 (10), pp. e0185862. Date of Electronic Publication: 2017 Oct 05 (Print Publication: 2017).
DOI:	10.1371/journal.pone.0185862
Abstrakt:	Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and elucidates a highly effective combination strategy in MAPK-dependent cancer, such as KRAS mutant tumors.
Databáze:	MEDLINE
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