2. Academic Validation
  3. CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors in drug resistant breast cancers through p21/p27 induction

CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors in drug resistant breast cancers through p21/p27 induction

  • Nat Commun. 2026 Jan 22;17(1):619. doi: 10.1038/s41467-025-67865-4.
Linjie Luo 1,  Yan Wang 1,  Tuyen Bui 1,  Xiaoting Jiang 1 2,  Mei-Kuang Chen 1,  Xiayu Rao 3,  Sepideh Mohammadhosseinpour 1,  Mi Li 1,  Serena Kim 1,  Rachel Y Kim 1,  Saba Kamaliasl 1,  Carmen W Ulizio 1,  Spyros Tsavachidis 4,  Juliana Navarro-Yepes 1,  Nicole M Kettner 1,  Hannah Wingate 5,  Funda Meric-Bernstam 6,  Kelly K Hunt 5,  Jing Wang 3,  Kerrie Faia 7,  Khandan Keyomarsi 8
Affiliations

Affiliations

  • 1 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 5 Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Blueprint Medicines Corporation, Cambridge, MA, USA.
  • 8 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
PMID: 41571637 DOI: 10.1038/s41467-025-67865-4
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.

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