Abstract 5979: TY-0540, a highly potent CDK2/4/6 inhibitor, attenuates acquired resistance against CDK4/6 inhibition

Abstract

Abstract The introduction of cyclin-dependent kinase (CDK) 4 and 6 dual inhibitors significantly improves the progression-free survival of patients with ER+/HER2- advanced or metastatic breast cancer. A large cohort of patients, however, eventually relapse to CDK4/6 therapy. To further empower the CDK therapy, simultaneous targeting of CDK2, CDK4, and CDK6 has been proposed as a new strategy based on the finding that abnormal activation of CDK2/CyclinE1 due to CCNE1 gene amplification is determined the key resistant mechanism to CDK4/6 inhibition. Here we present preclinical data of TY-0540, a novel CDK2/4/6 inhibitor for the treatment of breast cancer that is resistant to CDK4/6 inhibition. TY-0540 demonstrates high selectivity against CDK2, CDK4, and CDK6 compared to that of CDK1, CDK7, and CDK9 in a CDK panel screening. In vitro cell proliferation data shows that tumor cell lines OVCAR3 and HCC1806, both bearing CCNE1 amplification, are highly sensitive to TY-0540 treatment. To test the effectiveness of the clinical candidate compound on CDK4/6i resistance models, two Palbociclib resistant cell populations (T47D-R, HCC1428-R) were in-house generated via gradient exposure of the cells to Palbociclib. As expected, TY-0540 potently inhibits T47D-R and HCC1428-R cell proliferation whereas Palbociclib only confers mild interruption to cell proliferation. TY-0540 abolishes Rb phosphorylation at all its three phosphorylation sites and down-regulates E2F1, FOXM1, and c-Myc expression levels in the model cell line OVCAR3. Meanwhile, cell cycle analysis suggests the occurrence of strong G1 arrest at 24 hours after TY-0540 treatment. Consistent with the in vitro results, TY-0540 treatment confers extraordinary in vivo efficacy with a spectrum of tumor CDX mouse models and PDX models in mice. To examine the in vivo effectiveness of TY-0540 over resistance models to CDK4/6 inhibition, we developed Palbociclib-resistant MCF7 tumor model (Palbociclib-R-MCF7) through a combination of in vitro and in vivo evolution of the cells under the selection pressure of Palbociclib. In agreement with its mode of action, TY-0540 is able to suppress Palbociclib-R-MCF7 tumor growth and maintain tumor size at stable disease status. Taken together, we have identified a potent CDK2/4/6 inhibitor which may grant new therapeutic opportunities for cancer patients who relapse or refractory to CDK4/6 signaling blockage therapy. #Meihua Li and Chengshan Niu contributed equally to this work. *Jun Li, Meihua Li and Chengshan Niu are the correspondent authors. Citation Format: Meihua Li, Chengshan Niu, Mingtao Chen, Kaige Ji, Hui Xu, Shengli Dong, Yan Zhang, Qinguo Meng, Yuge Dou, Yijun Wang, Rui Wu, Yian Tu, Chao Zhou, Apeng Liang, Huan Wang, Rongzhen Ni, Aishen Gong, Hui Su, Mingyu Jiang, Feng Xing, Shaoqing Chen, Xiugui Chen, Jun Li, Yusheng Wu. TY-0540, a highly potent CDK2/4/6 inhibitor, attenuates acquired resistance against CDK4/6 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5979.