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Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants.
Brenan, Lisa; Andreev, Aleksandr; Cohen, Ofir; Pantel, Sasha; Kamburov, Atanas; Cacchiarelli, Davide; Persky, Nicole S; Zhu, Cong; Bagul, Mukta; Goetz, Eva M; Burgin, Alex B; Garraway, Levi A; Getz, Gad; Mikkelsen, Tarjei S; Piccioni, Federica; Root, David E; Johannessen, Cory M.
  • Brenan L; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Andreev A; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Cohen O; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Pantel S; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kamburov A; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Cacchiarelli D; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Persky NS; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Zhu C; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Bagul M; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Goetz EM; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Burgin AB; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Garraway LA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Getz G; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Mikkelsen TS; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Piccioni F; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Root DE; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Johannessen CM; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: johannes@broadinstitute.org.
Cell Rep ; 17(4): 1171-1183, 2016 10 18.
Article en En | MEDLINE | ID: mdl-27760319
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteína Quinasa 1 Activada por Mitógenos / Mutación Missense Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteína Quinasa 1 Activada por Mitógenos / Mutación Missense Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article