Gong Yuwen, Gao Dongyang, Shi Yibo, Fan Guangrui, Yu Xiaoquan, Yang Enguang, Cheng Hui, Tian Junqiang, Ding Hui, Liu Shanhui, Fu Shengjun, Tao Yan, Shui Yuan, Cheng Liang, Li Lanlan, Wang Zhiping
Institute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou, Gansu, China.
Department of Pathology and Laboratory Medicine, Department of Surgery (Urology), Brown University Warren Albert Medical School, Brown University Health, Providence, RI, USA.
Commun Biol. 2025 Jan 10;8(1):36. doi: 10.1038/s42003-024-07284-1.
The development of cisplatin resistance often results in a grim prognosis in advanced or recurrent bladder cancer. However, effective treatment strategies for cisplatin resistance have not been well established. Herein, we found that overactivation of SRC is associated with cisplatin-resistance. SRC activates hexokinase2 which up-regulates glycolysis and especially the pentose phosphate pathway that leading to increased nucleotide synthesis and NADPH production which can neutralize reactive oxygen species (ROS) induced by cisplatin, thereby protecting bladder cancer cells from cisplatin-induced DNA damage. This phenomenon was effectively reversed by knockout of SRC and inhibition of SRC activity by the SRC inhibitor, eCF506. Moreover, we constructed Cell-derived xenograft (CDX) and Patient-derived xenograft (PDX) from cisplatin-resistant bladder cancer patient. eCF506 exhibited excellent anti-tumor effects and effectively enhanced cisplatin-sensitivity. Altogether, our findings demonstrate that targeting SRC is a promising approach to overcome cisplatin-resistance in bladder cancer, and providing new insights for combination therapy in bladder cancer.
顺铂耐药的发展常常导致晚期或复发性膀胱癌的预后严峻。然而，针对顺铂耐药的有效治疗策略尚未完全确立。在此，我们发现SRC的过度激活与顺铂耐药相关。SRC激活己糖激酶2，己糖激酶2上调糖酵解，特别是磷酸戊糖途径，导致核苷酸合成增加和NADPH生成增加，这可以中和顺铂诱导的活性氧（ROS），从而保护膀胱癌细胞免受顺铂诱导的DNA损伤。通过敲除SRC以及使用SRC抑制剂eCF506抑制SRC活性，这种现象得到了有效逆转。此外，我们从顺铂耐药的膀胱癌患者构建了细胞衍生异种移植瘤（CDX）和患者衍生异种移植瘤（PDX）。eCF506表现出优异的抗肿瘤作用，并有效增强了顺铂敏感性。总之，我们的研究结果表明，靶向SRC是克服膀胱癌顺铂耐药的一种有前景的方法，并为膀胱癌的联合治疗提供了新的见解。
