Abstract：
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.
摘要：
奥希替尼耐药被认为是限制接受表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）治疗的患者生存益处的主要障碍。然而,获得性耐药的潜在机制尚不清楚.在这项研究中,我们报道,雌激素受体β(ERβ)在奥希替尼耐药的NSCLC中高表达,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）是去泛素化和上调NSCLC中ERβ的关键结合伴侣。ERβ通过减轻活性氧（ROS）积累促进奥希替尼耐药。我们发现ERβ在机制上抑制了过氧化物酶3（PRDX3）去氧化，从而赋予NSCLC奥希替尼耐药性。此外，我们提供的证据表明,ERβ的耗竭在体外和体内均能诱导NSCLC中的ROS积累并逆转奥希替尼耐药.因此，我们的结果表明，USP7介导的ERβ稳定抑制PRDX3SUMO化，以减轻ROS积累并促进奥希替尼耐药，提示靶向ERβ可能是克服NSCLC奥希替尼耐药的有效治疗策略.
