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- Title
Combating subclonal evolution of resistant cancer phenotypes.
- Authors
Brady, Samuel W.; McQuerry, Jasmine A.; Yi Qiao; 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 W.
- 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.
- Publication
Nature Communications, 2017, Vol 8, Issue 11, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-017-01174-3