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 Gray & 8 others Laura 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 journalArticle

19 Citations (Scopus)

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 languageEnglish (US)
Article number1231
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

phenotype
Chemotherapy
cancer
drugs
Phenotype
chemotherapy
breast
Pharmaceutical Preparations
Neoplasms
Breast Neoplasms
Drug Resistance
Drug Therapy
Immune system
RNA Sequence Analysis
Therapeutics
Refractory materials
Antigen Presentation
Tumors
immune systems
Drug Delivery Systems

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Brady, S. W., McQuerry, J. A., Qiao, Y., Piccolo, S. R., Shrestha, G., Jenkins, D. F., ... Bild, A. H. (2017). Combating subclonal evolution of resistant cancer phenotypes. Nature Communications, 8(1), [1231]. https://doi.org/10.1038/s41467-017-01174-3

Combating subclonal evolution of resistant cancer phenotypes. / Brady, Samuel W.; McQuerry, Jasmine A.; Qiao, Yi; Piccolo, Stephen R.; 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 Y.; Moos, Philip J.; Gray, Joe; Heiser, Laura; Buys, Saundra S.; Cohen, Adam L.; Johnson, W. Evan; Quinlan, Aaron R.; Marth, Gabor; Werner, Theresa L.; Bild, Andrea H.

In: Nature Communications, Vol. 8, No. 1, 1231, 01.12.2017.

Research output: Contribution to journalArticle

Brady, SW, McQuerry, JA, Qiao, Y, Piccolo, SR, Shrestha, G, Jenkins, DF, Layer, RM, Pedersen, BS, Miller, RH, Esch, A, Selitsky, SR, Parker, JS, Anderson, LA, Dalley, BK, Factor, RE, Reddy, CB, Boltax, JP, Li, DY, Moos, PJ, Gray, J, Heiser, L, Buys, SS, Cohen, AL, Johnson, WE, Quinlan, AR, Marth, G, Werner, TL & Bild, AH 2017, 'Combating subclonal evolution of resistant cancer phenotypes', Nature Communications, vol. 8, no. 1, 1231. https://doi.org/10.1038/s41467-017-01174-3
Brady SW, McQuerry JA, Qiao Y, Piccolo SR, Shrestha G, Jenkins DF et al. Combating subclonal evolution of resistant cancer phenotypes. Nature Communications. 2017 Dec 1;8(1). 1231. https://doi.org/10.1038/s41467-017-01174-3
Brady, Samuel W. ; McQuerry, Jasmine A. ; Qiao, Yi ; Piccolo, Stephen R. ; 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 Y. ; Moos, Philip J. ; Gray, Joe ; Heiser, Laura ; Buys, Saundra S. ; Cohen, Adam L. ; Johnson, W. Evan ; Quinlan, Aaron R. ; Marth, Gabor ; Werner, Theresa L. ; Bild, Andrea H. / Combating subclonal evolution of resistant cancer phenotypes. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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