Journal Article

CDK2 inhibition enhances CDK4/6 inhibitor antitumor activity in comprehensive breast cancer PDX model screen

Chen, Maxine M., Khazaei, Sima, Wu, Rentian, Ramsden, Philip, Luo, Linjie, Brown, Victoria, Muthuswamy, Lakshmi B., Feng, Ningping, Yuan, Liang, Keyomarsi, Khandan, Peng, David H., Marszalek, Joseph R., Rinne, Mikael L., Bristow, Christopher A., Ribich, Scott, Moore, Sydney, House, Nealia C., Wang, Fangyang, Yap, Timothy A., Faia, Kerrie L.

2025

Overview

Aberrant cyclin-dependent kinase 2 (CDK2) activity is implicated as a resistance mechanism to CDK4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. Using preclinical patient-derived xenograft models, the CDK2i + CDK4/6i combination was active broadly across CDK4/6i-resistant and -naïve HR+ and triple-negative breast cancer models. A novel, weighted mRNA expression signature involving CCND1 , CCNE1 , RB1 , and CDKN2A (p16) predicted response to combined inhibition of CDK2 and CDK4/6. Addition of endocrine therapy significantly enhanced antitumor activity in HR+ models, providing preclinical proof-of-concept for the broad antitumor activity of the triple combination. Early clinical data demonstrated activity of BLU-222, a potent and selective CDK2 inhibitor, both as monotherapy ( CCNE1 amplified) and in combination with ribociclib and fulvestrant in patients with HR+/HER2− breast cancer. These findings provide evidence that CDK2i combined with CDK4/6i can address multiple known mechanisms of resistance to CDK4/6i, enhancing antitumor responses in preclinical breast cancer models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154 / 631/67 / 692/4028 / Biomarkers / Biomedical and Life Sciences / Biomedicine / Breast cancer / Cancer Research / Cancer therapies / Cell Biology / Cell cycle / Cyclin-dependent kinases / Gene expression / Human Genetics / Oncology / Patients / Phase transitions