Luo Dandong, Wang Huashe, Liu Jun, Chen Xiaochuan, Xu Yucheng, Liang Yufan, Wang Guannan, Zheng Jiabo, Chen Yonghe, Wang Xinyou, Yu Zhaoliang, Lian Lei
Department of General Surgery (Gastric Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China; Department of Pathology, The First People's Hospital of Kashi Prefecture, Kashi, China.
Department of General Surgery (Gastric Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China.
Cancer Lett. 2025 Mar 31;613:217500. doi: 10.1016/j.canlet.2025.217500. Epub 2025 Jan 31.
Signet ring cell carcinoma (SRCC) poses a considerable challenge in terms of treatment, given its refractory nature and poor outcomes. Unlike other cancers, SRCC exhibits significant MDM2 copy number gains, with elevated MDM2 expression linked to poor prognosis. MDM2 inhibition induces a morphological transition in SRCC cells by suppressing E-cadherin degradation, which may render these cells vulnerable to a second drug. Using a high-throughput drug screen, our study demonstrated that the combination of MDM2 inhibitors with G2/M checkpoint inhibitors, including WEE1 or CHK1 inhibitors, can elicit a synergistic antitumor response in SRCC cells by inducing DNA damage. Furthermore, pharmacological inhibition of MDM2, WEE1, or CHK1 significantly impeded tumor growth in in vivo mouse models and organoids of SRCC. Collectively, our findings indicate that MDM2 inhibition-induced morphological changes may enhance the efficacy of G2/M checkpoint inhibitors, presenting a promising combined treatment for SRCC.
印戒细胞癌（SRCC）因其难治性和不良预后，在治疗方面构成了相当大的挑战。与其他癌症不同，SRCC表现出显著的MDM2拷贝数增加，MDM2表达升高与预后不良相关。MDM2抑制通过抑制E-钙黏蛋白降解诱导SRCC细胞发生形态转变，这可能使这些细胞对第二种药物敏感。通过高通量药物筛选，我们的研究表明，MDM2抑制剂与G2/M期检查点抑制剂（包括WEE1或CHK1抑制剂）联合使用，可通过诱导DNA损伤在SRCC细胞中引发协同抗肿瘤反应。此外，对MDM2、WEE1或CHK1的药理学抑制显著阻碍了SRCC体内小鼠模型和类器官中的肿瘤生长。总体而言，我们的研究结果表明，MDM2抑制诱导的形态变化可能增强G2/M期检查点抑制剂的疗效，为SRCC提供了一种有前景的联合治疗方法。
