Liu Chenlin, Fan Dong, Sun Jiahui, Li Guodong, Du Ruoxin, Zuo Xiaoshuang, Zhang Kuo, Zhang Wangqian, Wang Shuning, Li Xiaojv, Du Mingrui, Wang Donghui, Hao Qiang, Zhang Yingqi, Li Meng, Zhang Cun, Gao Yuan
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, 710032, Xi'an, People's Republic of China.
Department of Occupational and Environmental Health, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
J Nanobiotechnology. 2025 Jan 3;23(1):3. doi: 10.1186/s12951-024-03021-2.
CDK4/6i, the first-line drug for treating ERα-positive breast cancer, significantly improves clinical outcomes. However, CDK4/6i resistance often develops and remains a major hurdle, and the underlying mechanisms remain challenging to fully investigate. Here, we used Genome-wide CRISPR/Cas9 library screening combined with single-cell sequencing to screen for molecules mediating CDK4/6i resistance and identified METTL14 as a determinant of CDK4/6i sensitivity. Clinical samples and datasets were analyzed and in vitro and in vivo experiments were performed to confirm the critical function of METTL14 in CDK4/6i resistance. Mechanistically, METTL14 can induce an increase in E2F1 expression in breast cancer cells via an m6A IGF2BP2-dependent mechanism and thus promote CDK4/6i resistance. Furthermore, through a small molecule screen, a novel METTL14 inhibitor named WKYMVM, which can restore sensitivity to CDK4/6i in CDK4/6i-resistant breast cancer cells, was identified. Treatment with folate-conjugated liposomes targeting breast cancer cells that contained both a CDK4/6i and WKYMVM revealed the synergistic effect of METTL14 inhibition with CDK4/6i therapy in a CDK4/6i-resistant PDX model. Together, our findings reveal the mechanism of CDK4/6i resistance and provide a strategy for overcoming CDK4/6i resistance via METTL14 inhibition.
CDK4/6抑制剂作为治疗雌激素受体α（ERα）阳性乳腺癌的一线药物，显著改善了临床疗效。然而，CDK4/6抑制剂耐药性常常出现，仍然是一个主要障碍，其潜在机制仍难以全面研究。在此，我们使用全基因组CRISPR/Cas9文库筛选结合单细胞测序来筛选介导CDK4/6抑制剂耐药性的分子，并确定METTL14是CDK4/6抑制剂敏感性的决定因素。我们分析了临床样本和数据集，并进行了体外和体内实验，以证实METTL14在CDK4/6抑制剂耐药性中的关键作用。从机制上讲，METTL14可通过一种m6A-IGF2BP2依赖性机制诱导乳腺癌细胞中E2F1表达增加，从而促进CDK4/6抑制剂耐药性。此外，通过小分子筛选，我们鉴定出一种名为WKYMVM的新型METTL14抑制剂，它可以恢复CDK4/6抑制剂耐药的乳腺癌细胞对CDK4/6抑制剂的敏感性。用靶向乳腺癌细胞的叶酸偶联脂质体进行治疗，脂质体中同时含有CDK4/6抑制剂和WKYMVM，结果显示在CDK4/6抑制剂耐药的人源肿瘤异种移植（PDX）模型中，抑制METTL14与CDK4/6抑制剂治疗具有协同作用。总之，我们的研究结果揭示了CDK4/6抑制剂耐药的机制，并提供了一种通过抑制METTL14来克服CDK4/6抑制剂耐药性的策略。
