CDK2 inhibition enhances CDK4/6 inhibitor antitumor activity in comprehensive breast cancer PDX model screen
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.
Authors
- Maxine Chen (ORCID: https://orcid.org/0000-0001-7138-6228)
- David H. Peng (ORCID: https://orcid.org/0000-0003-0511-1888)
- Lakshmi Muthuswamy (ORCID: https://orcid.org/0000-0002-1533-317X)
- Christopher A. Bristow (ORCID: https://orcid.org/0009-0009-9266-6849)
- Mikael L. Rinne
- Linjie Luo (ORCID: https://orcid.org/0000-0002-2365-0327)
- Sima Khazaei (ORCID: https://orcid.org/0000-0002-0929-9366)
- Fangyang Wang (ORCID: https://orcid.org/0000-0003-3296-7278)
- Khandan Keyomarsi (ORCID: https://orcid.org/0000-0002-5440-0849)
- Joseph R. Marszalek (ORCID: https://orcid.org/0000-0003-2320-3209)
- Nealia C. House (ORCID: https://orcid.org/0000-0003-1264-7699)
- Philip Ramsden
- Scott Ribich
- Rentian Wu (ORCID: https://orcid.org/0000-0003-3862-6394)
- Timothy Anthony Yap (ORCID: https://orcid.org/0000-0002-2154-3309)
- Ningping Feng (ORCID: https://orcid.org/0000-0003-1917-9648)
- L. Kerrie (ORCID: https://orcid.org/0000-0002-6504-160X)
- Yuan Liang (ORCID: https://orcid.org/0000-0002-1861-4479)
- Victoria E. Brown (ORCID: https://orcid.org/0009-0005-1586-8392)
- Sydney Moore
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Blueprint Medicines (United States) (US)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1038/s41523-025-00851-7
- Citations
- 2
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 3.04