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Cell Rep DOI:10.1016/j.celrep.2016.09.061

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

Publication TypeJournal Article
Year of Publication2016
AuthorsBrenan, L, Andreev, A, Cohen, O, Pantel, S, Kamburov, A, Cacchiarelli, D, Persky, NS, Zhu, C, Bagul, M, Goetz, EM, Burgin, AB, Garraway, LA, Getz, G, Mikkelsen, TS, Piccioni, F, Root, DE, Johannessen, CM
JournalCell Rep
Volume17
Issue4
Pages1171-1183
Date Published2016 Oct 18
ISSN2211-1247
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.

DOI10.1016/j.celrep.2016.09.061
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27760319?dopt=Abstract

Alternate JournalCell Rep
PubMed ID27760319
PubMed Central IDPMC5120861
Grant ListU24 CA143845 / CA / NCI NIH HHS / United States