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Combating subclonal evolution of resistant cancer phenotypes #MMPMID29093439
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 JW; Heiser LM; Buys SS; Cohen AL; Johnson WE; Quinlan AR; Marth G; Werner TL; Bild AH
Nat Commun 2017[]; 8 (ä): ä PMID29093439show ga
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-? 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.