美国哈佛医学院丹娜法伯癌症研究院Pasi A. Jänne研究团队揭示了YAP介导的凋亡途径转录重编程引起治疗诱导的肿瘤休眠。这一研究成果2020年1月13日发表在国际学术期刊《癌细胞》上。

研究人员发现通过联合使用表皮生长因子受体（EGFR） / MEK抑制剂对EGFR酪氨酸激酶抑制剂（TKI）处理阻碍ERK1 / 2重新激活，这导致细胞进入以高YAP / TEAD活性为特征的衰老状休眠态而存活。YAP / TEAD通过调控上皮到间充质转化转录因子SLUG从而直接抑制促凋亡因子BMF，进而抑制药物诱导的凋亡。利用药物抑制YAP和TEAD或YAP1的基因缺失都能使得因EGFR / MEK抑制剂处理进入休眠的细胞重新凋亡。这项研究发现通过提高靶向疗法的初始疗效最终可能延长癌症患者的治疗反应。

据介绍，靶向表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）对EGFR突变型非小细胞肺癌的治疗，是一种有效的治疗策略，但对这一治疗的机制了解甚少。

附：英文原文

Title: Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

Author: Kari J. Kurppa, Yao Liu, Ciric To, Tinghu Zhang, Mengyang Fan, Amir Vajdi, Erik H. Knelson, Yingtian Xie, Klothilda Lim, Paloma Cejas, Andrew Portell, Patrick H. Lizotte, Scott B. Ficarro, Shuai Li, Ting Chen, Heidi M. Haikala, Haiyun Wang, Magda Bahcall, Yang Gao, Sophia Shalhout, Steffen Boettcher, Bo Hee Shin, Tran Thai, Margaret K. Wilkens, Michelle L. Tillgren, Mierzhati Mushajiang, Man Xu, Jihyun Choi, Arrien A. Bertram, Benjamin L. Ebert, Rameen Beroukhim, Pratiti Bandopadhayay, Mark M. Awad, Prafulla C. Gokhale, Paul T. Kirschmeier, Jarrod A. Marto, Fernando D. Camargo, Rizwan Haq, Cloud P. Paweletz, Kwok-Kin Wong, David A. Barbie, Henry W. Long, Nathanael S. Gray, Pasi A. Jnne

Issue&Volume: 2020/01/13

Abstract: 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 themechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivationfollowing EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that surviveby entering a senescence-like dormant state characterized by high YAP/TEAD activity.YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUGto 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. Enhancingthe initial efficacy of targeted therapies could ultimately lead to prolonged treatmentresponses in cancer patients.

DOI: 10.1016/j.ccell.2019.12.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30576-8