IF 5.3 2区 医学 Q1 ONCOLOGY
Ken Akao, Tatsuhiro Sato, Emi Mishiro-Sato, Satomi Mukai, Farhana Ishrat Ghani, Lisa Kondo-Ida, Kazuyoshi Imaizumi, Yoshitaka Sekido
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引用次数: 0

摘要

在间皮瘤中经常可以观察到 Hippo 抑瘤通路失活的现象,这会导致 YAP 和 TAZ(YAP/TAZ)转录辅激活因子的激活。YAP/TAZ与DNA结合蛋白TEAD家族成员形成复合物,激活转录,从而促进癌细胞生长和增殖。最近开发的 TEAD 抑制剂通过与 TEAD 结合抑制转录复合物的形成,从而显示出抗肿瘤活性;然而,TEAD 抑制剂对间皮瘤的抗肿瘤活性仍有待全面阐明。在这里,我们发现 TEAD 抑制剂 K-975 是一种泛 TEAD 抑制剂,能选择性地抑制间皮瘤细胞中 TEAD 结合蛋白(尤其是 YAP/TAZ)的结合。在使用一组间皮瘤细胞系进行的研究中,K-975 对 Hippo 失活的间皮瘤细胞有显著的生长抑制作用,但其中一些细胞系对 K-975 表现出了原发性耐药性。差异基因表达分析表明,对K-975耐药的细胞在K-975存在的情况下表现出MYC信号的激活,MYC过表达的细胞在体外和体内都表现出很强的耐药性。我们的研究揭示了间皮瘤细胞亚群以不依赖TEAD的方式增殖的特征,为成功开发Hippo通路失活的间皮瘤治疗策略提供了重要启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
TEAD-independent cell growth of Hippo-inactive mesothelioma cells: Unveiling resistance to TEAD inhibitor K-975 through MYC signaling activation.

Inactivation of the Hippo tumor suppressive pathway is frequently observed in mesothelioma, which leads to the activation of YAP and TAZ (YAP/TAZ) transcriptional coactivators. YAP/TAZ form complexes with TEAD family members, DNA-binding proteins, to activate transcription, which promotes cancer cell growth and proliferation. Recently developed TEAD inhibitors exhibit antitumor activity by inhibiting the formation of the transcription complex through binding to TEAD; however, the antitumor activity of TEAD inhibitors against mesothelioma remains to be fully elucidated. Here, we show that the TEAD inhibitor K-975 acts as a pan-TEAD inhibitor and selectively inhibits the binding of TEAD-binding proteins, especially YAP/TAZ, in mesothelioma cells. In studies using a panel of mesothelioma cell lines, K-975 showed a significant growth inhibitory effect on Hippo-inactivated mesothelioma cells, but some of these cell lines exhibited primary resistance to K-975. Differential gene expression analysis revealed that cells resistant to K-975 exhibited activation of MYC signaling in the presence of K-975, and cells overexpressed with MYC showed strong drug resistance, both in vitro and in vivo. Our study revealed the features of a subset of mesothelioma cells that proliferate in a TEAD-independent manner and provides important insights for the successful development of therapeutic strategies for mesothelioma with Hippo pathway inactivation.

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来源期刊
CiteScore
11.20
自引率
1.80%
发文量
331
审稿时长
3 months
期刊介绍: Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.
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