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Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer's ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.

Citation

Samuel W Brady, Jasmine A McQuerry, Yi Qiao, Stephen R Piccolo, Gajendra Shrestha, David F Jenkins, Ryan M Layer, Brent S Pedersen, Ryan H Miller, Amanda Esch, Sara R Selitsky, Joel S Parker, Layla A Anderson, Brian K Dalley, Rachel E Factor, Chakravarthy B Reddy, Jonathan P Boltax, Dean Y Li, Philip J Moos, Joe W Gray, Laura M Heiser, Saundra S Buys, Adam L Cohen, W Evan Johnson, Aaron R Quinlan, Gabor Marth, Theresa L Werner, Andrea H Bild. Combating subclonal evolution of resistant cancer phenotypes. Nature communications. 2017 Nov 01;8(1):1231


PMID: 29093439

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