哺乳动物SWI/SNF染色质重塑复合物促进EGFR突变肺癌对酪氨酸激酶抑制剂的耐药性。
Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer.
发表日期：2023 Aug 02
作者：
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 Jänne, Cigall Kadoch, Katerina A Politi
来源：
CANCER CELL
摘要：
酪氨酸激酶抑制剂（TKI）对于治疗EGFR突变的肺腺癌的奥西替尼等获得性耐药提高了持久疗效的限制，并且常常是由非遗传机制引起的。在这里，我们定义了对于奥西替尼敏感和耐药的EGFR突变细胞和患者来源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。通过对mSWI/SNF全基因组定位进行分析，我们确定了在耐药状态下既有共享的基因靶点，也有肿瘤细胞系特异的基因靶点。重要的是，SMARCA4/SMARCA2 mSWI/SNF ATP酶的基因和药物破坏通过抑制mSWI/SNF介导的调控细胞增殖、上皮-间质转化、上皮细胞分化和NRF2信号传导的细胞程序，使耐药模型的一部分重新对奥西替尼敏感。这些数据强调了mSWI/SNF复合物在支持TKI耐药中的作用，并提出了mSWI/SNF抑制剂在TKI耐药的肺癌中的潜在作用。版权所有© 2023年作者。由Elsevier Inc.发表。保留所有权利。
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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.