广西医科大学阳洁等研究人员合作发现，适配蛋白CEMIP通过激活SRC-YAP致癌模块降低小细胞肺癌的化疗敏感性。相关论文于2024年7月23日在线发表在《中国药理学报》杂志上。

研究人员表示，小细胞肺癌（SCLC）是一种难治性恶性肿瘤，因其在初期治疗后迅速复发而预后不佳。对SCLC的更有效治疗方法迫在眉睫。研究人员之前的发现表明，细胞迁移诱导透明质酸结合蛋白（CEMIP）功能上促进了SCLC细胞的增殖和转移。

研究人员探讨了CEMIP是否以及如何调节SCLC的化疗敏感性。通过GDSC数据库，研究人员发现CEMIP表达水平与SCLC细胞中几种常用化疗药物（顺铂、吉西他滨、氟尿嘧啶和环磷酰胺）的IC₅₀值呈正相关。研究人员证明了在SCLC细胞中过表达或敲低CEMIP分别导致顺铂或依托泊苷的IC₅₀值显著增加或减少。进一步研究显示，CEMIP作为适配蛋白在SCLC细胞中通过1-177氨基酸区和820-1361氨基酸区与SRC和YAP相互作用，促进SRC的自磷酸化，激活SRC，从而促进YAP与激活的SRC的相互作用，导致YAP的Y357位点磷酸化、蛋白质稳定性、核内积累及转录激活。

过表达SRC或YAP可抵消CEMIP敲低介导的SCLC细胞对顺铂和依托泊苷的敏感性增加。SRC抑制剂达沙替尼或YAP抑制剂Verteporfin与顺铂/依托泊苷（EP方案）的联合治疗在体外和体内均表现出优异的协同抗肿瘤效果。该研究表明，针对CEMIP/SRC/YAP复合体的靶向治疗是一种潜在的SCLC策略，并为未来的临床试验提供了合理的依据。

附：英文原文

Title: Adaptor protein CEMIP reduces the chemosensitivity of small cell lung cancer via activation of an SRC-YAP oncogenic module

Author: Shen, Xiao-ju, Wei, Hui-lan, Mo, Xiao-cheng, Mo, Xiao-xiang, Li, Li, He, Jing-chuan, Wei, Xin-yu, Qin, Xiao-jun, Xing, Shang-ping, Luo, Zhuo, Chen, Zhi-quan, Yang, Jie

Issue&Volume: 2024-07-23

Abstract: 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.

DOI: 10.1038/s41401-024-01342-4

Source: https://www.nature.com/articles/s41401-024-01342-4