Journal
CELL REPORTS
Volume 17, Issue 4, Pages 1171-1183Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.09.061
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Funding
- Carlos Slim Foundation in Mexico
- Melanoma Research Foundation
- William Guy Forbeck Research Foundation
- Broad Institute
- Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital
- NIH TCGA Genome Data Analysis Center [U24CA143845]
- Novartis
- Astellas
- BMS
- Merck
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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.
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