Li Pingping, Zhao Yufei, Lu Minghan, Chen Chengfei, Li Yongkun, Wang Lingling, Zeng Shulan, Peng Yan, Liang Hong, Zhang Guohai
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China.
School of Comprehensive Health Management, Xihua University, Chengdu, China.
Cell Death Dis. 2025 May 12;16(1):374. doi: 10.1038/s41419-025-07708-8.
Polo-like kinase 1 (PLK1) signaling drives tumor malignancy and chemotherapy resistance, which is an unmet clinical need. Recruiting PLK1 to the central spindle during anaphase is necessary for its function in promoting cancer cell proliferation, which is achieved by binding to microtubule-associated protein regulating of cytokinesis (PRC1) located in the spindle. However, the role of PLK1/PRC1 signaling in chemotherapy resistance is unknown. In this study, we identified a small molecule B4 which inhibited PLK1/PRC1 signaling through disrupting the formation of PLK1/PRC1 protein complexes. In the presence of blocking PLK1/PRC1 signaling, enhanced sensitivity of drug-resistant tumors to traditional chemotherapy was found. Suppression of PLK1 activity by B4 inhibited disease progression in allograft models, and combination with cisplatin elicited dramatic regression of drug-resistant tumors. Our findings provide a promising strategy to target the PLK1 signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in non-small cell lung cancer (NSCLC).
Polo样激酶1（PLK1）信号传导驱动肿瘤恶性进展和化疗耐药性，这是一个尚未满足的临床需求。在后期将PLK1募集到纺锤体中央对于其促进癌细胞增殖的功能是必要的，这是通过与位于纺锤体中的细胞分裂调节微管相关蛋白（PRC1）结合来实现的。然而，PLK1/PRC1信号传导在化疗耐药性中的作用尚不清楚。在本研究中，我们鉴定出一种小分子B4，它通过破坏PLK1/PRC1蛋白复合物的形成来抑制PLK1/PRC1信号传导。在阻断PLK1/PRC1信号传导的情况下，发现耐药肿瘤对传统化疗的敏感性增强。B4抑制PLK1活性可抑制同种异体移植模型中的疾病进展，并且与顺铂联合使用可使耐药肿瘤显著消退。我们的研究结果提供了一种靶向PLK1信号级联的有前景的策略，并证明了一种增强非小细胞肺癌（NSCLC）对化疗敏感性的潜在方式。
