Q901, A Selective Cdk7 Inhibitor, A Potential New Strategy For Primary And Cdk4/6 Inhibitor Resistant Er-Positive Breast Cancer

Abstract CDK4/6 inhibitors, in combination with hormone therapy, has made a breakthrough in treatment of hormone receptor-positive, HER2-negative metastatic breast cancers. However, in clinical practice, a substantial number of patients who responded to CDK4/6 inhibitors eventually develop resistance within 2-3 years. Current knowledge of the molecular mechanisms of CDK4/6 inhibitor resistance is under investigation , with the loss of function of the retinoblastoma (RB) protein the most frequently observed change in resistance to CDK4/6 inhibitors. RB loss of function by CDK4/6 inhibitors appears an irreversible mechanism of resistance while gain of cyclin E, and overexpression of CDK2 reducing cyclin D1-CDK4/6 dependency which results in the resistant cell to re-enter into s-phase. Thus, inhibition of the cyclin E-CDK2 axis may be effective in overcoming resistance to CDK4/6 inhibitors. We report a novel treatment strategy that targets Cyclin-dependent kinase 7 (CDK7) in CDK4/6 inhibitor-resistant, ER+ breast cancer. Q901 is a novel highly-selective inhibitor against CDK7 and demonstrates good functional inhibition of CDK activating kinase (CAK) activities leading to activation of CDK4, 6 and CDK2 in vitro and in vivo. Q901, monotherapy, effectively inhibited tumor growth in ER+ breast cancer xenograft model as well as CDK4/6 inhibitor resistant PDX model. The results suggest a potential for Q901 in treatment of hormone receptor-positive, HER2-negative metastatic breast cancer, regardless of resistance status to CDK4/6 inhibitors. Citation Format: Donghoon Yu, Yeejin Jeon, Dongsik Park, Mooyoung Seo, Wongyun Ahn, Jaeseung Kim, Kiyean Nam. Q901, a selective CDK7 inhibitor, a potential new strategy for primary and CDK4/6 inhibitor resistant ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1953.