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. Gray, Laura M. Heiser, Saundra S. Buys, Adam L. Cohen, W. Evan Johnson, Aaron R. Quinlan, Gabor Marth, Theresa L. Werner and Andrea H. Bild ()
Additional contact information
Samuel W. Brady: University of Utah
Jasmine A. McQuerry: University of Utah
Yi Qiao: University of Utah
Stephen R. Piccolo: University of Utah
Gajendra Shrestha: University of Utah
David F. Jenkins: Boston University
Ryan M. Layer: University of Utah
Brent S. Pedersen: University of Utah
Ryan H. Miller: University of Utah
Amanda Esch: Oregon Health & Science University
Sara R. Selitsky: University of North Carolina
Joel S. Parker: University of North Carolina
Layla A. Anderson: University of Utah
Brian K. Dalley: Huntsman Cancer Institute
Rachel E. Factor: Huntsman Cancer Hospital
Chakravarthy B. Reddy: University of Utah
Jonathan P. Boltax: University of Utah
Dean Y. Li: University of Utah
Philip J. Moos: University of Utah
Joe W. Gray: Oregon Health & Science University
Laura M. Heiser: Oregon Health & Science University
Saundra S. Buys: University of Utah
Adam L. Cohen: University of Utah
W. Evan Johnson: University of Utah
Aaron R. Quinlan: University of Utah
Gabor Marth: University of Utah
Theresa L. Werner: University of Utah
Andrea H. Bild: University of Utah

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01174-3

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DOI: 10.1038/s41467-017-01174-3

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