biostudies-literatureAissa AFNCI NIH HHSNIGMS NIH HHSU.S. Department of Health & Human Services | National Institutes of Health1628https://www.ebi.ac.uk/biostudies/studies/S-EPMC7955121biostudies-literatureUnknown12(1)Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolNature communicationsSingle-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer.PMC7955121R01 CA211095R01CA211095R35GM131707R35 GM131707Ariss MMGajda AMGreen SJConrardy RDIslam ABMMKGo CCBenevolenskaya EVRader AEPasquinelli MValyi-Nagy KLopez-Bigas NFrolov MVAissa AFRubio-Perez CFeldman LEfalseSingle-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer.Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabol2021-01-01T00:00:00Z2021 Mar2026-05-01T06:02:08.542Z2022-02-09T18:07:56.117ZS-EPMC79551213371261510.1038/s41467-021-21884-z