Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer.
Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer.
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单细胞转录变化与癌症中药物耐受性和对联合疗法的反应相关。
DOI：
10.1038/s41467-021-21884-z
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发表时间：
2021-03-12
影响因子：
16.6
通讯作者：
Benevolenskaya EV
中科院分区：
文献类型：
--
作者：
Aissa AF;Islam ABMMK;Ariss MM;Go CC;Rader AE;Conrardy RD;Gajda AM;Rubio-Perez C;Valyi-Nagy K;Pasquinelli M;Feldman LE;Green SJ;Lopez-Bigas N;Frolov MV;Benevolenskaya EV
酪氨酸激酶抑制剂被发现在临床上对某些携带受体酪氨酸激酶体细胞突变的癌症亚群患者有效。然而，临床反应的持续时间往往有限，患者最终会产生耐药性。在这里，我们使用单细胞RNA测序来证明细胞系、异种移植肿瘤和患者肿瘤中存在多个癌细胞亚群。这些亚群表现出表观遗传变化和不同的治疗敏感性。在耐药细胞群和药物敏感细胞之间表达差异的基因中，反复被过度代表的本体包括上皮到间质转化、上皮发育、囊泡介导的转运、药物代谢和胆固醇稳态。我们展示了使用LINCS数据库对已识别的标记物进行分析，以预测和功能验证靶向选定的耐药细胞群的小分子。与EGFR抑制剂联合，克唑替尼抑制EGFR抑制剂耐受克隆的定义子集的出现。在这项研究中，我们描述了与药物耐受性和抑制特定耐受细胞亚群相关的变化谱。有人提出，非小细胞肺癌（NSCLC）对靶向治疗的耐药是由于细胞群的非均匀性。在这里，作者使用单细胞RNA-seq分析临床前NSCLC模型，并鉴定耐药细胞状态和亚群，以及相关基因。
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. It has been proposed that resistance to targeted therapies in non-small cell lung carcinoma (NSCLC) is due to a nonhomogeneous cell population. Here the authors analyse preclinical NSCLC models using single-cell RNA-seq and identify drug tolerant cell states and subpopulations, as well as associated genes.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
16.6
作者：
Angelidis, Ilias;Simon, Lukas M.;Schiller, Herbert B.
通讯作者：
Schiller, Herbert B.
影响因子：
3.7
作者：
Becker L;Liu NC;Averill MM;Yuan W;Pamir N;Peng Y;Irwin AD;Fu X;Bornfeldt KE;Heinecke JW
通讯作者：
Heinecke JW
影响因子：
9
作者：
Che Y;Wang J;Li Y;Lu Z;Huang J;Sun S;Mao S;Lei Y;Zang R;Sun N;He J
通讯作者：
He J
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y