Qu Xiaojuan, Ou Hongyue, Wu Yifan, Jiang Biao, Song Xiaoling
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Bioorg Chem. 2025 Aug;163:108641. doi: 10.1016/j.bioorg.2025.108641. Epub 2025 Jun 4.
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases. Among NSCLC patients, approximately 15-30 % harbor activating mutations in the Epidermal Growth Factor Receptor (EGFR), making them eligible for treatment with tyrosine kinase inhibitors (TKIs) like osimertinib, which has shown significant therapeutic benefits. However, acquired resistance to these therapies remains a major challenge in improving long-term clinical outcomes, underscoring the urgent need for novel strategies to address treatment resistance. In this study, we investigated the therapeutic potential of Amiloride (MK-870), a sodium channel inhibitor, as an adjuvant to EGFR-targeted therapies for NSCLC. Our findings demonstrate that MK-870 exhibits synergistic effects with EGFR PROTACs and small-molecule inhibitors, significantly enhancing antitumor activity in NSCLC cell lines. We identified α-ENaC (encoded by SCNN1A) as a key regulator of EGFR stability, with high α-ENaC expression correlating with reduced sensitivity to EGFR. MK-870 achieves dual downregulation of EGFR at both transcriptional and protein levels via targeted inhibition of sodium channel proteins. Furthermore, MK-870 enhances lysosomal activity in multiple NSCLC cell lines and EGFR-overexpressing NIH/3 T3 cells-a phenomenon potentially linked to its inhibition of sodium‑hydrogen exchanger (NHE) to promote cellular acidification. Mechanistically, the resultant acidification promotes apoptosis while simultaneously enhancing lysosome-mediated degradation of EGFR proteins by PROTAC molecules. Collectively, MK-870 synergizes with EGFR-targeting agents through coordinated modulation of sodium channel proteins and NHE-mediated pH homeostasis. These novel insights highlight MK-870 as a promising adjuvant for overcoming EGFR-targeted therapeutic resistance in NSCLC, offering a new avenue for improving patient outcomes in this challenging disease.
肺癌仍然是全球癌症相关死亡的主要原因，其中非小细胞肺癌（NSCLC）占大多数病例。在NSCLC患者中，约15%-30%的患者表皮生长因子受体（EGFR）存在激活突变，这使得他们有资格接受酪氨酸激酶抑制剂（TKIs）治疗，如奥希替尼，该药物已显示出显著的治疗益处。然而，对这些疗法产生获得性耐药仍然是改善长期临床结果的主要挑战，这凸显了迫切需要新的策略来应对治疗耐药性。在本研究中，我们研究了钠通道抑制剂氨氯地平（MK-870）作为NSCLC的EGFR靶向治疗辅助药物的治疗潜力。我们的研究结果表明，MK-870与EGFR PROTACs和小分子抑制剂具有协同作用，显著增强了NSCLC细胞系中的抗肿瘤活性。我们确定α-ENaC（由SCNN1A编码）是EGFR稳定性的关键调节因子，α-ENaC高表达与对EGFR的敏感性降低相关。MK-870通过靶向抑制钠通道蛋白在转录和蛋白质水平上实现EGFR的双重下调。此外，MK-870增强了多种NSCLC细胞系和EGFR过表达的NIH/3T3细胞中的溶酶体活性——这一现象可能与其抑制钠氢交换体（NHE）以促进细胞酸化有关。从机制上讲，由此产生的酸化促进细胞凋亡，同时增强PROTAC分子对EGFR蛋白的溶酶体介导降解。总体而言，MK-870通过协同调节钠通道蛋白和NHE介导的pH稳态与EGFR靶向药物发挥协同作用。这些新见解突出了MK-870作为克服NSCLC中EGFR靶向治疗耐药性的有前景的辅助药物，为改善这种具有挑战性疾病的患者预后提供了一条新途径。
