Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants

Lisa Brenan; Aleksandr Andreev; Ofir Cohen; Sasha Pantel; Atanas Kamburov; Davide Cacchiarelli; Nicole S. Persky; Cong Zhu; Mukta Bagul; Eva M. Goetz; Alex B. Burgin; Levi A. Garraway; Gad Getz; Tarjei S. Mikkelsen; Federica Piccioni; David E. Root; Cory M. Johannessen

doi:10.1016/j.celrep.2016.09.061

Cell Reports (Oct 2016)

Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants

Lisa Brenan,
Aleksandr Andreev,
Ofir Cohen,
Sasha Pantel,
Atanas Kamburov,
Davide Cacchiarelli,
Nicole S. Persky,
Cong Zhu,
Mukta Bagul,
Eva M. Goetz,
Alex B. Burgin,
Levi A. Garraway,
Gad Getz,
Tarjei S. Mikkelsen,
Federica Piccioni,
David E. Root,
Cory M. Johannessen

Affiliations

Lisa Brenan: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Aleksandr Andreev: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Ofir Cohen: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Sasha Pantel: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Atanas Kamburov: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Davide Cacchiarelli: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Nicole S. Persky: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Cong Zhu: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Mukta Bagul: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Eva M. Goetz: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Alex B. Burgin: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Levi A. Garraway: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Gad Getz: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Tarjei S. Mikkelsen: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Federica Piccioni: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
David E. Root: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Cory M. Johannessen: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

DOI: https://doi.org/10.1016/j.celrep.2016.09.061
Journal volume & issue: Vol. 17, no. 4
pp. 1171 – 1183

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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