Faculty, Staff and Student Publications
Language
English
Publication Date
12-3-2025
Journal
npj Breast Cancer
DOI
10.1038/s41523-025-00851-7
PMID
41339342
PMCID
PMC12675586
PubMedCentral® Posted Date
12-3-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Cancer, Drug discovery, Oncology
Published Open-Access
yes
Recommended Citation
House, Nealia C; Chen, Maxine M; Khazaei, Sima; et al., "CDK2 Inhibition Enhances CDK4/6 Inhibitor Antitumor Activity in Comprehensive Breast Cancer PDX Model Screen" (2025). Faculty, Staff and Student Publications. 5974.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5974
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