@article{18d6973f20cf4fcb9fd8a3850ebedc3d,
title = "Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants",
abstract = "Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants. Gain-of-function ERK2 mutants induced variable responses to RAF-, MEK-, and ERK-directed therapies, providing a reference for future treatment decisions. Tumor-associated mutations spatially clustered in two ERK2 effector-recruitment domains yet produced mutants with opposite phenotypes. This approach articulates an allele-characterization framework that can be scaled to meet the goals of genome-guided oncology.",
keywords = "cancer, ERK, functional biology, MAPK, precision medicine, precision oncology, rare mutants",
author = "Lisa Brenan and Aleksandr Andreev and Ofir Cohen and Sasha Pantel and Atanas Kamburov and Davide Cacchiarelli and Persky, {Nicole S.} and Cong Zhu and Mukta Bagul and Goetz, {Eva M.} and Burgin, {Alex B.} and Garraway, {Levi A.} and Gad Getz and Mikkelsen, {Tarjei S.} and Federica Piccioni and Root, {David E.} and Johannessen, {Cory M.}",
note = "Funding Information: We thank Xiaolan Zhang and Robert Lintner for technical assistance. We thank Amit Majithia, Amanda Walker, Brett Tomson, William G. Kaelin, Jr., Nicole Persky, and the Broad Institute Research Associate/Associate Computational Biologist Journal Club for manuscript review. We thank Adam Tracy for assistance in data management. This work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico. This work was supported by a Career Development Award from the Melanoma Research Foundation (C.M.J.), a Collaborative Research Award from the William Guy Forbeck Research Foundation (C.M.J.), a Broad Institute Scientific Projects to Accelerate Research and Collaboration (T.S.M.), by the Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital (G.G.), and by the NIH TCGA Genome Data Analysis Center (U24CA143845, G.G.). L.A.G. is a consultant for Foundation Medicine, Novartis, Boehringer Ingelheim, Third Rock; an equity holder in Foundation Medicine; and a member of the Scientific Advisory Board at Warp Drive. L.A.G. receives sponsored research support from Novartis, Astellas, BMS, and Merck. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = oct,
day = "18",
doi = "10.1016/j.celrep.2016.09.061",
language = "English",
volume = "17",
pages = "1171--1183",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}
