Combating subclonal evolution of resistant cancer phenotypes

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. GrayLaura M. Heiser, Saundra S. Buys, Adam L. Cohen, W. Evan Johnson, Aaron R. Quinlan, Gabor Marth, Theresa L. Werner, Andrea H. Bild

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


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.

Original languageEnglish (US)
Article number1231
JournalNature communications
Issue number1
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


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