Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer
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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
Cantley, Lewis C
Date Issued
December 2017
Journal
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Citation
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.
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Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1158/2159-8290.CD-17-0679
