Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway
Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway
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DOI：
10.1016/j.ccell.2019.12.006
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发表时间：
2020-01-13
期刊：
影响因子：
50.3
通讯作者：
Janne, Pasi A.
中科院分区：
文献类型：
--
作者：
Kurppa, Kari J.;Liu, Yao;Janne, Pasi A.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗EGFR突变型非小细胞肺癌后，消除肿瘤休眠是一种有吸引力的治疗策略，但对这一过程的机制知之甚少。EGFR TKI治疗后，通过EGFR/MEK联合抑制阻断ERK 1/2再活化，可发现通过进入衰老样休眠状态（以高雅普/TEAD活性为特征）而存活的细胞。雅普/TEAD与上皮-间充质转化转录因子SLUG结合，直接抑制促凋亡BMF，限制药物诱导的细胞凋亡。雅普和TEAD的药理学共抑制或YAP 1的遗传缺失都通过增强EGFR/MEK抑制诱导的细胞凋亡来消耗休眠细胞。提高靶向治疗的初始疗效最终可能导致癌症患者的治疗反应延长。
Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.