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.
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Brenan
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Andreev
authors.affiliation: 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.
authors.forename: Ofir
authors.initials: O
authors.lastname: Cohen
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Sasha
authors.initials: S
authors.lastname: Pantel
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Atanas
authors.initials: A
authors.lastname: Kamburov
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Cacchiarelli
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Persky
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhu
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Mukta
authors.initials: M
authors.lastname: Bagul
authors.affiliation: 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.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goetz
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
authors.affiliation: 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.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Piccioni
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: johannes@broadinstitute.org.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Johannessen
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015203:Reproducibility of Results
chemical_list: D047428:Protein Kinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6
keywords: ERK; MAPK; cancer; functional biology; precision medicine; precision oncology; rare mutants