CDK2 Inhibitor Blu-222 Synergizes With CDK4/6 Inhibitors in Drug Resistant Breast Cancers Through p21/p27 Induction

Authors

Linjie Luo
Yan Wang
Tuyen Bui
Xiaoting Jiang
Mei-Kuang Chen
Xiayu Rao
Sepideh Mohammadhosseinpour
Mi Li
Serena Kim
Rachel Y Kim
Saba Kamaliasl
Carmen W Ulizio
Spyros Tsavachidis
Juliana Navarro-Yepes
Nicole M Kettner
Hannah Wingate
Funda Meric-Bernstam
Kelly K Hunt
Jing Wang
Kerrie Faia
Khandan Keyomarsi

Language

English

Publication Date

1-22-2026

Journal

Nature Communications

DOI

10.1038/s41467-025-67865-4

PMID

PMC12828054

PMCID

PMC12828054

PubMedCentral® Posted Date

1-22-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2- and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated p21 and p27 expression, enhanced p21 binding to CDK2 as well as p21 and p27 binding to CDK4. CRISPR knockout of p21 or p27 in palbociclib-resistant cells eliminated this synergy. Further, RNA sequencing revealed that combination treatment upregulated senescence and interferon pathways, providing mechanistic insight into the observed therapeutic synergy.

Keywords

Humans, Female, Cyclin-Dependent Kinase 4, Animals, Drug Resistance, Neoplasm, Cyclin-Dependent Kinase Inhibitor p21, Piperazines, Cyclin-Dependent Kinase 6, Cell Line, Tumor, Pyridines, Purines, Mice, Aminopyridines, Drug Synergism, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 2, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Apoptosis, Acrylamides, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Breast cancer, Cancer, Cancer therapy

Published Open-Access

yes

Recommended Citation

Luo, Linjie; Wang, Yan; Bui, Tuyen; et al., "CDK2 Inhibitor Blu-222 Synergizes With CDK4/6 Inhibitors in Drug Resistant Breast Cancers Through p21/p27 Induction" (2026). Faculty, Staff and Student Publications. 5975.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5975