|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Brenan, 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|
|Date Published||2016 Oct 18|
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.
|Alternate Journal||Cell Rep|
|PubMed Central ID||PMC5120861|
|Grant List||U24 CA143845 / CA / NCI NIH HHS / United States|