@article{335cb09858d14beb9630cbf6336fabb6,
title = "Combating subclonal evolution of resistant cancer phenotypes",
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.",
author = "Brady, {Samuel W.} and McQuerry, {Jasmine A.} and Yi Qiao and Piccolo, {Stephen R.} and Gajendra Shrestha and Jenkins, {David F.} and Layer, {Ryan M.} and Pedersen, {Brent S.} and Miller, {Ryan H.} and Amanda Esch and Selitsky, {Sara R.} and Parker, {Joel S.} and Anderson, {Layla A.} and Dalley, {Brian K.} and Factor, {Rachel E.} and Reddy, {Chakravarthy B.} and Boltax, {Jonathan P.} and Li, {Dean Y.} and Moos, {Philip J.} and Gray, {Joe W.} and Heiser, {Laura M.} and Buys, {Saundra S.} and Cohen, {Adam L.} and Johnson, {W. Evan} and Quinlan, {Aaron R.} and Gabor Marth and Werner, {Theresa L.} and Bild, {Andrea H.}",
note = "Funding Information: We thank the anonymous patients used in our study for their generous contributions to research. We acknowledge Patricia Bild for inspiring this research. We also thank the Huntsman Cancer Institute Biorepository, which collected most of the biospecimens in this study. We acknowledge Dr. David Bowtell for helpful feedback on this project. S.W. B. was supported by NLM training grant 5T15LM007124. This research was supported by NIH 4U01CA164720-05 and U54 CA 209978-01 to A.H.B. and U24CA209999 to G.T. M. We also acknowledge University of Utah core facility experimental support, including the flow cytometry core (funded by NIH grant 1S10RR026802-01) and cell imaging core (funded by NIH grant 1S10RR024761-01).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41467-017-01174-3",
language = "English (US)",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}