小细胞肺癌（SCLC）是一种顽固性恶性肿瘤，由于初始治疗反应后快速复发，预后较差。 SCLC 迫切需要更有效的治疗方法。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 细胞增殖和转移。在本研究中，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IC50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 IC50 值显着增加或降低。我们进一步发现，CEMIP在SCLC细胞中作为衔接蛋白，分别通过1-177 aa结构域和820-1361 aa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，从而促进两者之间的相互作用YAP 和激活的 SRC，导致 Y357 磷酸化、蛋白质稳定性、核积累和 YAP 转录激活增加。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抑制剂达沙替尼或YAP抑制剂维替泊芬与顺铂/依托泊苷联合（EP方案）在体外和体内对SCLC表现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的发展提供了理论依据。© 2024。作者，获得上海研究院独家许可中国科学院药物研究所、中国药理学会.

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 IC50 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 IC50 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.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.