Abstract 3064: The interaction of calcium-sensing receptor with KIF11 enhances cisplatin resistance in lung adenocarcinoma

Abstract Lung cancer remains the deadliest form of cancer globally, and non-small cell lung cancer (NSCLC) accounts for 80%-85%. Chemotherapy remains the foundational treatment for NSCLC, with platinum-based regimens serving as the primary first-line therapy for advanced stages of the disease. Cisplatin is a widely used platinum drug with strong broad-spectrum anticancer activity. However, the development of chemotherapy resistance frequently results in treatment failure. Consequently, further research into the mechanisms underlying tumor chemoresistance is crucial for enhancing our understanding of tumor cell biology. This research will aid in identifying new resistance-related genes and molecules, facilitate the development of novel chemotherapeutic agents, and improve treatment regimens. In this study, we first established two cisplatin-resistant lung adenocarcinoma cell lines, A549-DDP and H1299-DDP, by exposing them to escalating concentrations of cisplatin. Through transcriptome analysis and examination of the correlation between gene expression and the prognosis of lung adenocarcinoma patients treated with chemotherapy, we discovered that CaSR was significantly upregulated in cisplatin-resistant LUAD cells. Additionally, high expressions of CaSR were closely associated with poor prognosis in LUAD patients receiving chemotherapy. As a member of the Gprotein-coupled receptor (GPCR) family, the role of CaSR in tumor chemoresistance has been infrequently reported. To further investigate this, we generated LUAD cell lines with stable overexpression of CaSR and confirmed its essential role in cisplatin resistance. Meanwhile, we observed that CaSR knockdown significantly enhanced the sensitivity of cisplatin-resistant LUAD cells. Importantly, a combination of cisplatin with the CaSR inhibitor NPS-2143 significantly inhibited the growth of cisplatin-resistant LUAD cells in vitro and in vivo. Furthermore, CaSR was found to be involved in the cell cycle of cisplatin-resistant LUAD cells and affected the protein levels of BRCA1 and cyclin B1. Moreover, we have observed an interaction between CaSR and KIF11. In LUADcells, KIF11 was identified as a crucial hub within the CaSR signaling pathway, regulating the expression of cyclin B1 and BRCA1 and promoting cisplatin resistance. Our study highlighted the therapeutic potential of targeting CaSR to mitigate the chemotherapy resistance of LUAD. Furthermore, it explores a novel mechanism underlying chemoresistance in LUAD and provides essential experimental evidence, presenting the case as a promising therapeutic target for overcoming cisplatin resistance in clinical settings. This work was supported by the NSFC Project (82173336, 81972766, 81972420), The Science and Technology Project of Shenzhen(JCYJ20210324104214040), the Medical Research Innovation Project (G030410001). Citation Format: Fuhao Wang, Ming Chang, Xiao Zhang, Xiaoyi Li, Zhiying Chen, Wei Zhang, Jian Zhang. The interaction of calcium-sensing receptor with KIF11 enhances cisplatin resistance in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3064.