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Published on: May 26, 2017
Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants
Lisa Brenan1, Aleksandr Andreev1, Ofir Cohen2
1The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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.
Insights
Characterizing tumor mutations in MAPK1/ERK2 reveals functionally impactful variants beyond frequency. This work provides a framework for understanding cancer mutations and guiding personalized therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Tumor-specific genomic data can guide cancer treatment, but many disease-associated mutants lack functional characterization.
- Understanding the biological impact of these mutants is crucial for effective therapeutic strategies.
Purpose of the Study:
- To functionally characterize missense mutants of MAPK1/ERK2, a key effector in oncogenic signaling pathways.
- To identify functionally impactful ERK2 mutants in human tumors and assess their therapeutic relevance.
Main Methods:
- Systematic functional characterization of nearly all MAPK1/ERK2 missense mutants.
- Assessing gain- and loss-of-function phenotypes of identified mutants.
- Evaluating the response of gain-of-function mutants to RAF-, MEK-, and ERK-directed therapies.
Main Results:
- Discovery of rare gain- and loss-of-function ERK2 mutants in human tumors.
- Demonstration that mutational frequency alone does not identify all functionally significant mutants.
- Variable responses of gain-of-function ERK2 mutants to targeted therapies.
- Spatial clustering of tumor-associated mutations in ERK2 effector-recruitment domains, yielding opposite phenotypes.
Conclusions:
- Functional characterization is essential for identifying impactful cancer mutations beyond frequency.
- ERK2 mutants exhibit diverse functional impacts and variable responses to targeted therapies.
- An allele-characterization framework can be developed for genome-guided oncology.
