Zhou Dongdong, Tang Er'jiang, Wang Wenjun, Xiao Youban, Huang Jianming, Liu Jie, Zheng Chao, Zhang Kai, Hu Ruxia, Wang Feiqi, Xiong Peng, Chu Xin, Li Weisong, Liu Dongqin, Zeng Xiangfu, Zheng Dexian, Wang Liefeng, Zheng Yong, Zhang Shuyong
Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China; School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China.
Center for Clinical Research and Translational Medicine, Yangpu Hospital, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China; Institute of Gastrointestinal Surgery and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China.
Cell Rep Med. 2025 Jun 17;6(6):102158. doi: 10.1016/j.xcrm.2025.102158. Epub 2025 May 30.
Targeted therapies for advanced microsatellite stable (MSS) subtype colorectal cancer (MSS-CRC) remain a clinical challenge. Here, we show that death receptor 5 (DR5) is elevated in both MSS and microsatellite instability-high (MSI-H) colorectal cancer (CRC) cohorts, highlighting its potential as a clinical target. Oba01, a clinical-stage DR5-targeting antibody-drug conjugate (ADC) delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE), shows superior efficacy in CRC cell lines, patient-derived xenografts and their corresponding organoids, irrespective of MSS or MSI-H status. Importantly, our functional multi-omics analysis reveals that the cell cycle pathway and cyclin-dependent kinases (CDKs) are key synergistic targets of Oba01's tumor-killing activity. We further show that Oba01 synergizes with the Food and Drug Administration (FDA)-approved CDK inhibitor abemaciclib in clinically relevant in vivo models. This synergy is also observed with other CDK inhibitors, underscoring the potential of combining Oba01 with CDK inhibition as a therapeutic strategy for advanced CRC, particularly the refractory MSS subtype.
晚期微卫星稳定（MSS）亚型结直肠癌（MSS-CRC）的靶向治疗仍然是一项临床挑战。在此，我们表明死亡受体5（DR5）在MSS和微卫星高度不稳定（MSI-H）结直肠癌（CRC）队列中均升高，突出了其作为临床靶点的潜力。Oba01是一种临床阶段的靶向DR5的抗体药物偶联物（ADC），可递送破坏微管的药物单甲基奥瑞他汀E（MMAE），在CRC细胞系、患者来源的异种移植瘤及其相应类器官中显示出卓越疗效，无论其MSS或MSI-H状态如何。重要的是，我们的功能多组学分析表明，细胞周期途径和细胞周期蛋白依赖性激酶（CDK）是Oba01肿瘤杀伤活性的关键协同靶点。我们进一步表明，在临床相关的体内模型中，Oba01与美国食品药品监督管理局（FDA）批准的CDK抑制剂阿贝西利具有协同作用。在其他CDK抑制剂中也观察到这种协同作用，强调了将Oba01与CDK抑制联合作为晚期CRC尤其是难治性MSS亚型的治疗策略的潜力。
