顺铂（DDP）常用于治疗包括肺腺癌（LUAD）在内的非小细胞肺癌（NSCLC），其临床无效的主要原因是化疗耐药。在这里，我们的目的是研究 LUAD 细胞化疗耐药的新机制，重点关注钙敏感受体 (CaSR)。在本研究中，在 DDP 耐药的 LUAD 细胞中检测到高 CaSR 表达，CaSR 表达升高与接受化疗的 LUAD 患者预后不良密切相关。 CaSR高表达的LUAD细胞对顺铂的敏感性降低，顺铂治疗联合CaSR抑制可抑制DDP耐药的LUAD细胞的生长，并伴有体内外BRCA1和cyclin B1蛋白表达的变化。此外，还发现了 CaSR 和 KIF11 之间的相互作用。重要的是，抑制KIF11导致BRCA1和细胞周期蛋白B1的蛋白水平降低，增强了DDP耐药的LUAD细胞对顺铂的敏感性，而CaSR没有明显降低。在这里，我们的研究结果确立了 CaSR 通过调节细胞周期蛋白 B1 和 BRCA1 在促进 LUAD 细胞顺铂耐药中的关键作用，并确定 KIF11 作为介质，强调了靶向 CaSR 克服 LUAD 化疗耐药性的潜在治疗价值。© 作者。

Cisplatin (DDP) is commonly used in the treatment of non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), and the primary cause for its clinical inefficacy is chemoresistance. Here, we aimed to investigate a novel mechanism of chemoresistance in LUAD cells, focusing on the calcium-sensing receptor (CaSR). In this study, high CaSR expression was detected in DDP-resistant LUAD cells, and elevated CaSR expression is strongly correlated with poor prognosis in LUAD patients receiving chemotherapy. LUAD cells with high CaSR expression exhibited decreased sensitivity to cisplatin, and the growth of DDP-resistant LUAD cells was inhibited by cisplatin treatment in combination with CaSR suppression, accompanied by changes in BRCA1 and cyclin B1 protein expression both in vitro and in vivo. Additionally, an interaction between CaSR and KIF11 was identified. Importantly, suppressing KIF11 resulted in decreased protein levels of BRCA1 and cyclin B1, enhancing the sensitivity of DDP-resistant LUAD cells to cisplatin with no obvious decrease in CaSR. Here, our findings established the critical role of CaSR in promoting cisplatin resistance in LUAD cells by modulating cyclin B1 and BRCA1 and identified KIF11 as a mediator, highlighting the potential therapeutic value of targeting CaSR to overcome chemoresistance in LUAD.© The author(s).