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

  • NPJ Breast Cancer. 2025 Dec 3;11(1):135. doi: 10.1038/s41523-025-00851-7.
Nealia C House  #  1 ,  Maxine M Chen  #  2 ,  Sima Khazaei  3 ,  Victoria Brown  2 ,  Philip Ramsden  2 ,  David H Peng  3 ,  Sydney Moore  2 ,  Liang Yuan  2 ,  Rentian Wu  2 ,  Fangyang Wang  3 ,  Linjie Luo  4 ,  Ningping Feng  3 ,  Christopher A Bristow  3 ,  Timothy A Yap  5 ,  Khandan Keyomarsi  4 ,  Joseph R Marszalek  3 ,  Scott Ribich  2 ,  Mikael L Rinne  2 ,  Lakshmi B Muthuswamy  2 ,  Kerrie L Faia  2
Affiliations
  • 1. Blueprint Medicines Corporation, Cambridge, MA, USA. [email protected].
  • 2. Blueprint Medicines Corporation, Cambridge, MA, USA.
  • 3. TRACTION - Translational Research to AdvanCe Therapeutics and Innovation in ONcology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Investigational Cancer Therapeutics, Therapeutic Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • # Contributed equally.
PMID: 41339342 DOI: 10.1038/s41523-025-00851-7
Abstract

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.

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