Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China.
Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Acta Pharmacol Sin. 2024 Dec;45(12):2657-2671. doi: 10.1038/s41401-024-01342-4. Epub 2024 Jul 23.
Small cell lung cancer (SCLC) is a recalcitrant malignancy with dismal prognosis due to rapid relapse after an initial treatment response. More effective treatments for SCLC are desperately needed. Our previous studies showed that cell migration-inducing hyaluronan binding protein (CEMIP) functionally promotes SCLC cell proliferation and metastasis. In this study, we investigated whether and how CEMIP regulates the chemosensitivity of SCLC. Through the GDSC database, we found that CEMIP expression levels were positively correlated with the IC values of several commonly used chemotherapeutic drugs in SCLC cells (cisplatin, gemcitabine, 5-fluorouracil and cyclophosphamide). We demonstrated that overexpression or knockdown of CEMIP in SCLC cells resulted in a notable increase or reduction in the IC value of cisplatin or etoposide, respectively. We further revealed that CEMIP functions as an adaptor protein in SCLC cells to interact with SRC and YAP through the 1-177 aa domain and 820-1361 aa domain, respectively, allowing the autophosphorylation of Y416 and activation of SRC, thus facilitating the interaction between YAP and activated SRC, and resulting in increased phosphorylation of Y357, protein stability, nuclear accumulation and transcriptional activation of YAP. Overexpressing SRC or YAP counteracted the CEMIP knockdown-mediated increase in the sensitivity of SCLC cells to cisplatin and etoposide. The combination of the SRC inhibitor dasatinib or the YAP inhibitor verteporfin and cisplatin/etoposide (EP regimen) displayed excellent synergistic antitumor effects on SCLC both in vitro and in vivo. This study demonstrated that targeted therapy against the CEMIP/SRC/YAP complex is a potential strategy for SCLC and provides a rationale for the development of future clinical trials with translational prospects.
小细胞肺癌（SCLC）是一种难治性恶性肿瘤，由于初始治疗反应后迅速复发，预后不佳。迫切需要更有效的 SCLC 治疗方法。我们之前的研究表明，细胞迁移诱导透明质酸结合蛋白（CEMIP）在功能上促进 SCLC 细胞的增殖和转移。在这项研究中，我们研究了 CEMIP 是否以及如何调节 SCLC 的化疗敏感性。通过 GDSC 数据库，我们发现 CEMIP 表达水平与 SCLC 细胞中几种常用化疗药物（顺铂、吉西他滨、5-氟尿嘧啶和环磷酰胺）的 IC 值呈正相关。我们证明，SCLC 细胞中 CEMIP 的过表达或敲低分别导致顺铂或依托泊苷的 IC 值显著增加或降低。我们进一步揭示，CEMIP 在 SCLC 细胞中作为衔接蛋白，分别通过 1-177aa 结构域和 820-1361aa 结构域与 SRC 和 YAP 相互作用，允许 Y416 的自身磷酸化和 SRC 的激活，从而促进 YAP 和激活的 SRC 之间的相互作用，并导致 Y357 的磷酸化增加、蛋白稳定性增加、核内积累增加和 YAP 的转录激活。过表达 SRC 或 YAP 抵消了 CEMIP 敲低介导的 SCLC 细胞对顺铂和依托泊苷敏感性的增加。SRC 抑制剂 dasatinib 或 YAP 抑制剂 verteporfin 与顺铂/依托泊苷（EP 方案）联合应用在体外和体内对 SCLC 均显示出优异的协同抗肿瘤作用。这项研究表明，针对 CEMIP/SRC/YAP 复合物的靶向治疗是 SCLC 的一种潜在策略，并为未来具有转化前景的临床试验提供了开发的依据。
