Abstract 7199: Synergistic anticancer effects of milciclib and mirdametinib: mechanistic insights into cell cycle arrest, DNA damage, and senescence

Abstract Milciclib, a cyclin-dependent kinase (CDK) inhibitor, has recently been identified as a modulator of pre-mRNA splicing, broadening its therapeutic potential. However, resistance to CDK inhibitors frequently arises due to activation of compensatory pathways, such as the MEK-ERK signaling cascade, which drives unchecked cell cycle progression and circumvents critical checkpoints. RNA sequencing of Milciclib-treated cells revealed significant upregulation of the MEK pathway, highlighting a potential resistance mechanism and supporting the strategy of targeting MEK in combination therapy. To address this challenge, we investigated the combination of Milciclib with the MEK inhibitor Mirdametinib (PD-0325901) across various cancer types, including colorectal cancer. The combination synergistically inhibited cancer cell proliferation by inducing cell cycle arrest at G0/G1 and G2/M phases. It also impaired homologous recombination repair, as evidenced by reduced RAD51 levels, and enhanced DNA damage (γH2AX). Furthermore, Mirdametinib alone and in combination with Milciclib promoted cellular senescence, characterized by the upregulation of p16 and p21. In vivo, the combination treatment significantly inhibited tumor growth in animal models. These findings highlight the complementary mechanisms of action of Milciclib and Mirdametinib. The synergy observed in this combination therapy provides a strong rationale for further clinical investigation. Citation Format: Xinyu Pei, Juifang Fan, Anh Nguyen Nguyen, Hannah Neiger, Imran A. Khan, Vladimir Bezrookove, Yu Zhou, Maureen Veilleux, Lily S. Wang, Valerie A. Gerriets, John K. Cusick, Pierre Y. Desprez, Li Zheng, Mohammed Kashani-Sabet, Binghui Shen, Yihui Shi. Synergistic anticancer effects of milciclib and mirdametinib: mechanistic insights into cell cycle arrest, DNA damage, and senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7199.