Combating subclonal evolution of resistant cancer phenotypes

• DOI: 10.1038/s41467-017-01174-3
• Publication Date: 2017-10-26T10:27:36Z
• Authors: 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. R...; 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; Andrea H. Bild
• Keywords: Tumour heterogeneity

Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic phenotypic subclonal evolution of four cancers through years treatment better understand how become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk single-cell RNA sequencing reveal acquisition malignant phenotypes after treatment, including enhanced mesenchymal growth factor signaling, which may promote resistance, decreased antigen presentation TNF-α enable immune system avoidance. Some these pre-exist in pre-treatment subclones that dominant chemotherapy, indicating selection for phenotypes. Post-chemotherapy cells effectively treated with drugs targeting These findings highlight cancer's ability evolve phenotypically suggest a phenotype-targeted strategy adapts as it evolves.