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Targeting CDK2 in CDK4/6 inhibitor-resistant HR-positive/HER2-negative breast cancer

Award Number: R01CA316243
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Targeting CDK2 in CDK4/6 inhibitor-resistant HR-positive/HER2-negative breast cancer - Project Summary Hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2-) breast cancer (BC) represents 65-75% of all new cases, with a sharp decline in 5-year survival for metastatic (MBC) disease. The current standard of care for HR+/HER2- MBC combines hormonal therapy (HT) with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), which block retinoblastoma (RB) phosphorylation, reinforce cell cycle arrest, and suppress tumor growth. Despite substantial benefit, nearly all patients eventually develop resistance, underscoring the need for new targeted therapies. Resistance to CDK4/6i is genetically diverse, making single approaches unlikely to be effective across all tumors. Since CDK2 acts downstream of CDK4/6 to inactivate RB, next-generation selective CDK2 inhibitors (CDK2i) with improved tolerability represent a promising therapeutic strategy, and several are currently tested in early-phase clinical trials. Our preliminary data with PF-07104091 CDK2i monotherapy revealed clinical benefit in a group of patients with CDK4/6i-resistant HR+/HER2- MBC, with efficacy independent of RB but associated with TP53 status. Complementary studies in patient-derived cell lines (PDCLs) demonstrated that CDK2i acts independently of RB, reducing DNA replication, inducing DNA damage, and triggering apoptosis. These observations raise four fundamental questions: (1) How do genetic background and treatment history shape CDK2i mechanisms of action? (2) What pharmacodynamic markers reliably capture CDK2 activity? (3) Which combination strategies most effectively enhance CDK2i efficacy, particularly in CDK4/6i-resistant models? and (4) What mechanisms drive resistance to CDK2i? The distinct mechanisms of CDK2i and CDK4/6i in HR+/HER2- MBC suggest potential synergy through concurrent targeting of the G1/S and G2/M checkpoints. We hypothesize that CDK2i-CDK4/6i combinations will outperform single agents, with benefit shaped by the stage of CDK4/6i treatment and RB1 or TP53 status. Leveraging our unique PDCLs panel and integrated clinical-translational expertise, we propose to develop a comprehensive framework to understand CDK2 inhibition. Aim 1 will define the molecular mechanisms and pharmacodynamic markers of CDK2 inhibition using PDCLs and xenografts representing diverse genetic and treatment contexts, coupled with phosphoproteomic profiling. Human tumor xenografts in immunodeficient mice recapitulate key features of patient tumors and provide critical information on therapeutic efficacy and toxicity unavailable from in vitro models. Aim 2 will identify rational combination strategies, evaluating CDK2i in combination with CDK4/6i, selective CDK4i, endocrine therapy, or S-phase targeting chemotherapy, while delineating the roles of RB1 and TP53 in shaping response. Aim 3 will uncover mechanisms of CDK2i resistance and validate them in paired CDK2i-sensitive and -resistant models. Successful completion of these studies will inform ongoing clinical trials of selective CDK2 inhibitors and accelerate their translation into improved patient outcomes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $660,843 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	000	1	9/9/2026	NEW	$660,843
														Subtotal = $660,843

Grand Total All Awards = $660,843

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Targeting CDK2 in CDK4/6 inhibitor-resistant HR-positive/HER2-negative breast cancer

Award Number: R01CA316243

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/09/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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