哈佛医学院Matthew G. Oser课题组的一项最新研究研制了细胞周期蛋白A/B RxL抑制剂靶向G1–S检查点受损的癌症。该研究于2025年8月20日发表于国际一流学术期刊《自然》杂志上。

在这里，课题组研究人员开发了细胞渗透性，口服生物可利用的大环肽，抑制RxL介导的细胞周期蛋白与其底物的相互作用。Cyclin A和Cyclin B RxL基序的双重抑制剂（Cyclin A/Bi）选择性地杀死SCLC细胞和其他具有高E2F活性的癌细胞。基因筛选显示，细胞周期蛋白A/Bi通过细胞周期蛋白B-和CDK2依赖性纺锤体组装检查点激活诱导细胞凋亡。从机制上讲，Cyclin A/Bi通过阻断Cyclin A-E2F和Cyclin B-MYT1 RxL相互作用来过度激活E2F和Cyclin B。值得注意的是，周期蛋白A/Bi促进了新形态周期蛋白B-CDK2复合物的形成，从而驱动纺锤体组装检查点激活和有丝分裂细胞死亡。最后，口服周期蛋白A/Bi在化疗耐药的SCLC患者来源的异种移植物中显示出明显的抗肿瘤活性。这些发现揭示了细胞周期蛋白A/Bi触发细胞凋亡的功能获得机制，并支持它们在E2F驱动的癌症中发展。

据悉，小细胞肺癌（SCLCs）包含RB1和TP53几乎普遍的功能缺失突变，损害G1-S检查点并导致E2F活性失调。其他癌症类似地通过CDKN2A的缺失或细胞周期蛋白D或细胞周期蛋白E的扩增破坏G1-S检查点，也导致过度的E2F活性。尽管E2F激活对于细胞周期进程至关重要，但过度激活会促进细胞凋亡，呈现出治疗脆弱性。细胞周期蛋白通过一个保守的疏水性贴片与带有短线性RxL基序的底物结合。Cyclin A通过依赖rxl的相互作用抑制E2F，当这种相互作用被破坏时，会过度激活E2F。然而，这种基板界面仍然难以定位。

附：英文原文

Title: Targeting G1–S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors

Author: Singh, Shilpa, Gleason, Catherine E., Fang, Min, Laimon, Yasmin N., Khivansara, Vishal, Xie, Shanhai, Durmaz, Yavuz T., Sarkar, Aniruddha, Ngo, Kenneth, Savla, Varunika, Li, Yixiang, Abu-Remaileh, Muhannad, Li, Xinyue, Locquet, Marie-Anais, Tuladhar, Bishma, Odeh, Ranya, Hamkins-Indik, Frances, He, Daphne, Membreno, Miles W., Nosrati, Meisam, Gushwa, Nathan N., Leung, Siegfried S. F., Fraga-Walton, Breena, Hernandez, Luis, Baldomero, Miguel P., Lent, Bryan M., Spellmeyer, David, Luna, Joshua F., Hoang, Dalena, Gritsenko, Yuliana, Chand, Manesh, DeMart, Megan K., Metobo, Sammy, Bhatt, Chinmay, Shapiro, Justin A., Yang, Kai, Dupper, Nathan J., Bockus, Andrew T., Fang, Jinshu, Bambal, Ramesh, Cremin, Peadar, Doench, John G., Aggen, James B., Liu, Li-Fen, Levin, Bernard, Wang, Evelyn W., Vendrell, Iolanda, Fischer, Roman, Kessler, Benedikt, Gokhale, Prafulla C., Signoretti, Sabina, Spektor, Alexander, Kreatsoulas, Constantine, Evangelista, Marie, Singh, Rajinder, Earp, David J., Nijhawan, Deepak, Garcia, Pablo D., Oser, Matthew G.

Issue&Volume: 2025-08-20

Abstract: Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1–S checkpoint and leading to dysregulated E2F activity1. Other cancers similarly disrupt the G1–S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity2,3. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis4,5,6,7,8,9, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs10,11,12,13. Cyclin A represses E2F through an RxL-dependent interaction10,14, which, when disrupted, hyperactivates E2F15. However, this substrate interface has remained difficult to target. Here we developed cell-permeable, orally bioavailable macrocyclic peptides that inhibit RxL-mediated interactions of cyclins with their substrates. Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A–E2F and cyclin B–MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B–CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers.

DOI: 10.1038/s41586-025-09433-w

Source: https://www.nature.com/articles/s41586-025-09433-w