生物
体细胞
表观遗传学
癌症研究
抗药性
酪氨酸激酶
医学
癌症
癌细胞
肿瘤微环境
转录因子
药品
基因
转录组
细胞
转录调控
基因表达调控
信号转导
药理学
遗传学
作者
Alexandre Ferro Aissa,Abul B. M. M. K. Islam,Majd M. Ariss,Cammille C. Go,Alexandra E. Rader,Ryan D. Conrardy,Alexa M. Gajda,Carlota Rubio-Perez,Klara Valyi-Nagy,Mary Pasquinelli,Lawrence Eric Feldman,Stefan J. Green,Nuria Lopez-Bigas,Maxim V. Frolov,Elizaveta V. Benevolenskaya
标识
DOI:10.1038/s41467-021-21884-z
摘要
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 metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.
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