小柯机器人

美国耶鲁大学医学院Katerina A. Politi以及美国麻省理工学院和哈佛大学布罗德研究所Cigall Kadoch课题组合作发现，哺乳动物SWI/SNF染色质重塑复合物促进EGFR突变肺癌中酪氨酸激酶抑制剂(TKI)的抗性。相关论文于2023年8月3日发表于国际顶尖学术期刊《癌细胞》杂志上。

他们定义了对奥西替尼敏感和耐药的EGFR突变细胞和患者衍生模型的染色质可及性和基因调控特征，并揭示了哺乳动物SWI/SNF染色质重塑复合物在TKI耐药中的作用。通过分析mSWI/SNF全基因组定位，他们确定了耐药状态下的共享和癌细胞系特异性基因靶点。重要的是，SMARCA4/SMARCA2 mSWI/SNF atp酶的遗传和药理学破坏通过抑制mSWI/SNF介导的控制细胞增殖、上皮细胞向间质转化、上皮细胞分化和NRF2信号传导的细胞程序的调节，使一部分耐药模型对奥西替尼重新敏感。

这些数据强调了mSWI/SNF复合物在支持TKI耐药中的作用，并提示mSWI/SNF抑制剂在TKI耐药肺癌中的潜在效用。

据悉，对TKI的获得性耐药，如用于治疗EGFR突变型肺腺癌的奥西替尼，限制了长期疗效，并且通常由非遗传机制引起。

附：英文原文

Title: Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

Author: Fernando J. de Miguel, Claudia Gentile, William W. Feng, Shannon J. Silva, Akshay Sankar, Francisco Exposito, Wesley L. Cai, Mary Ann Melnick, Camila Robles-Oteiza, Madeline M. Hinkley, Jeanelle A. Tsai, Antja-Voy Hartley, Jin Wei, Anna Wurtz, Fangyong Li, Maria I. Toki, David L. Rimm, Robert Homer, Craig B. Wilen, Andrew Z. Xiao, Jun Qi, Qin Yan, Don X. Nguyen, Pasi A. Jnne, Cigall Kadoch, Katerina A. Politi

Issue&Volume: 2023-08-03

Abstract: Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.

DOI: 10.1016/j.ccell.2023.07.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00245-3

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx