Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling
Peter Kreuzaler, Matthew A. Clarke, Elizabeth J. Brown, Catherine H. Wilson, Roderik M. Kortlever, Nir Piterman, Trevor Littlewood, Gerard I. Evan, Jasmin Fisher
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Source: Crossref
Published: Oct 14, 2019
DOI: 10.1073/pnas.1903485116
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Significance Breast cancer remains a leading cause for cancer-related mortality worldwide. All breast cancers, including the more difficult-to-treat, higher-grade, and triple-negative subtypes of breast cancer, exhibit strong genetic heterogeneity, which hampers treatment and fuels relapse. Our study advances the development of successful treatment approaches by unravelling the mechanistic basis of one form of heterogeneity arising from mutualism between high- and low-Myc–expressing clones in breast cancer. We use this mechanistic understanding to build an executable in silico model of oncogenic Myc/Ras/p53/Wnt signal cross talk for each Myc-expressing clone, separately and together, and then use this model to identify potential therapeutic vulnerabilities, which we then verify experimentally.
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