Combating Subclonal Evolution of Resistant Cancer Phenotypes

Authors

Samuel W. Brady, University of Utah
Jasmine A. McQuerry, University of Utah
Yi Qiao, University of Utah
Stephen Piccolo, Brigham Young UniversityFollow
Gajendra Shrestha, University of Utah
David F. Jenkins, Boston University
Ryan M. Layer, The 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 Li, University of Utah
Philip J. Moos, University of Utah
Joe W. Gray, Oregon Health and Science University
Laura M. Heiser, University of Utah
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

Keywords

Metastatic breast cancer, acquired drug resistance, growth factor signaling

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.

Original Publication Citation

Brady SW, McQuerry JA, Qiao Y, Piccolo SR, Shrestha G, Jenkins D, Layer RM, Pedersen BS, Miller R, Esch A, Selitsky S, Parker J, Anderson L, Dalley BK, Factor RE, Reddy CB, Boltax J, Li DY, Moos PJ, Gray JW, Heiser LM, Buys SS, Cohen AL, Johnson WE, Quinlan AR, Marth G, Werner TL, and Bild AH. Combating subclonal evolution of resistant cancer phenotypes. Nature Communications, 2017 Nov 1;8(1):1231. doi: 10.1038/s41467-017-01174-3

BYU ScholarsArchive Citation

Brady, Samuel W.; McQuerry, Jasmine A.; Qiao, Yi; Piccolo, Stephen; Shrestha, Gajendra; Jenkins, David F.; Layer, Ryan M.; Pedersen, Brent S.; Miller, Ryan H.; Esch, Amanda; Selitsky, Sara R.; Parker, Joel S.; Anderson, Layla A.; Dalley, Brian K.; Factor, Rachel E.; Reddy, Chakravarthy B.; Boltax, Jonathan P.; Li, Dean; Moos, Philip J.; Gray, Joe W.; Heiser, Laura M.; Buys, Saundra S.; Cohen, Adam L.; Johnson, W. Evan; Quinlan, Aaron R.; Marth, Gabor; Werner, Theresa L.; and Bild, Andrea H., "Combating Subclonal Evolution of Resistant Cancer Phenotypes" (2017). Faculty Publications. 7413.
https://scholarsarchive.byu.edu/facpub/7413

Document Type

Peer-Reviewed Article

Publication Date

2017-11-01

Publisher

Nature Research

Language

English

College

Life Sciences

Department

Biology

University Standing at Time of Publication

Associate Professor

Copyright Use Information

https://lib.byu.edu/about/copyright/