Li Lifeng, Xue Wenhua, Shen Zhibo, Liu Jie, Hu Min, Cheng Zhenyong, Wang Yuxing, Chen Yulu, Chang Hao, Liu Yingyi, Liu Bin, Zhao Jie
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Internet Medical and System Applications of National Engineering Laboratory, Zhengzhou, Henan, China.
Mol Ther Oncolytics. 2020 Jun 23;18:215-225. doi: 10.1016/j.omto.2020.06.013. eCollection 2020 Sep 25.
Therapeutic targeting of advanced or metastatic non-small-cell lung cancer (NSCLC) represents a major goal of clinical treatment. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in cell cycle progression and is associated with oncogenesis in a large spectrum of cancer types, including NSCLC. Volasertib (BI 6727) is a potent, selective, PLK1 inhibitor that is currently under phase 2 clinical trials with modest antitumor activity against solid tumors. As the combination of volasertib with pemetrexed does not improve efficacy for NSCLC treatment, it is crucial to identify compounds that could enhance efficacy with volasertib. Immunomodulatory drugs (IMiDs) bind to E3 ligase CRBN and repurposes it to ubiquitinate other proteins as neo-substrates, representing an effective treatment for hematologic malignancies. In this study, by screening IMiDs, we found that a novel CRBN modulator, CC-885, can synergistically inhibit NSCLC with volasertib both and . This synergistic effect overcomes volasertib resistance caused by PLK1 mutations and is compromised in CRBN-or p97-depleted cells. Mechanistically, CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation, thereby enhancing the sensitivity of NSCLC to volasertib. In conclusion, our findings reveal that PLK1 is a neo-substrate of CUL4-CRBN induced by CC-885 and represent a combinational approach for treating NSCLC.
晚期或转移性非小细胞肺癌（NSCLC）的治疗靶点是临床治疗的主要目标。Polo样激酶1（PLK1）是细胞周期进程中一种重要的有丝分裂激酶，在包括NSCLC在内的多种癌症类型的肿瘤发生过程中发挥作用。沃拉塞替布（BI 6727）是一种强效、选择性的PLK1抑制剂，目前正处于2期临床试验阶段，对实体瘤具有一定的抗肿瘤活性。由于沃拉塞替布与培美曲塞联合使用并不能提高NSCLC的治疗效果，因此确定能够增强沃拉塞替布疗效的化合物至关重要。免疫调节药物（IMiDs）与E3连接酶CRBN结合，并将其重新用于泛素化其他蛋白质作为新底物，是血液系统恶性肿瘤的一种有效治疗方法。在本研究中，通过筛选IMiDs，我们发现一种新型CRBN调节剂CC-885能够与沃拉塞替布协同抑制NSCLC。这种协同效应克服了由PLK1突变引起的沃拉塞替布耐药性，并且在CRBN或p97缺失的细胞中受到损害。从机制上讲，CC-885选择性地促进CRBN和p97依赖性的PLK1泛素化和降解，从而增强NSCLC对沃拉塞替布的敏感性。总之，我们的研究结果表明PLK1是CC-885诱导的CUL4-CRBN的新底物，为NSCLC的治疗提供了一种联合治疗方法。
