Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer
Author(s)Murphy, Charles J.; Karreth, Florian A.; Elemento, Olivier; Toker, Alex; Wulf, Gerburg M.; Cantley, Lewis C.; Yang, Kangkang; Liu, Hui; Emdal, Kristina Bennet; White, Forest M; Cantley, Lewis C; ... Show more Show less
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Triple-negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expression or oncoprotein-containing fusions, respectively, as well as frameshift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated. Although the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNA-seq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine–guided TNBC treatment.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology
American Association for Cancer Research (AACR)
Liu, Hui, Charles J. Murphy, Florian A. Karreth, Kristina B. Emdal, Forest M. White, Olivier Elemento, Alex Toker, Gerburg M. Wulf, and Lewis C. Cantley. “Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer.” Cancer Discovery 8, no. 3 (December 4, 2017): 354–369.
Author's final manuscript