Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
Cancer Lett. 2024 Feb 1;582:216587. doi: 10.1016/j.canlet.2023.216587. Epub 2023 Dec 13.
Osimertinib resistance is regarded as a major obstacle limiting survival benefits for patients undergoing treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, the underlying mechanisms of acquired resistance remain unclear. In this study, we report that estrogen receptor β (ERβ) is highly expressed in osimertinib-resistant NSCLC and plays a pivotal role in promoting osimertinib resistance. We further identified ubiquitin-specific protease 7 (USP7) as a critical binding partner that deubiquitinates and upregulates ERβ in NSCLC. ERβ promotes osimertinib resistance by mitigating reactive oxygen species (ROS) accumulation. We found that ERβ mechanistically suppresses peroxiredoxin 3 (PRDX3) SUMOylation and thus confers osimertinib resistance onto NSCLC. Furthermore, we provide evidence showing that depletion of ERβ induces ROS accumulation and reverses osimertinib resistance in NSCLC both in vitro and in vivo. Thus, our results demonstrate that USP7-mediated ERβ stabilization suppresses PRDX3 SUMOylation to mitigate ROS accumulation and promote osimertinib resistance, suggesting that targeting ERβ may be an effective therapeutic strategy to overcome osimertinib resistance in NSCLC.
奥希替尼耐药被认为是限制表皮生长因子受体 (EGFR)-突变型非小细胞肺癌 (NSCLC) 患者接受治疗后生存获益的主要障碍。然而，获得性耐药的潜在机制仍不清楚。在这项研究中，我们报告雌激素受体β (ERβ) 在奥希替尼耐药的 NSCLC 中高度表达，并在促进奥希替尼耐药中发挥关键作用。我们进一步确定泛素特异性蛋白酶 7 (USP7) 是一种关键的结合伴侣，可在 NSCLC 中去泛素化和上调 ERβ。ERβ 通过减轻活性氧 (ROS) 积累来促进奥希替尼耐药。我们发现 ERβ 通过抑制过氧化物酶 3 (PRDX3) 的 SUMO 化来抑制 PRDX3 的 SUMO 化，从而赋予 NSCLC 奥希替尼耐药性。此外，我们提供的证据表明，ERβ 的耗竭会在体外和体内引起 ROS 积累，并逆转 NSCLC 中的奥希替尼耐药性。因此，我们的研究结果表明，USP7 介导的 ERβ 稳定化通过抑制 PRDX3 SUMO 化来减轻 ROS 积累并促进奥希替尼耐药，表明靶向 ERβ 可能是克服 NSCLC 奥希替尼耐药的有效治疗策略。
