Abstract 426: Dual CDK4/6 and CDK7 inhibition: A synergistic strategy to overcome resistance and enhance anti-tumor immunity in breast cancer

Abstract Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved outcomes for patients with hormone receptor-positive (HR+) breast cancer. However, resistance to CDK4/6i limits their long-term efficacy, and their monotherapy has shown limited impact in triple-negative breast cancer (TNBC). Here, we present a novel therapeutic strategy combining CDK4/6i and CDK7 inhibitors (CDK7i) to address these limitations. Using a comprehensive suite of approaches—including live-cell imaging, RNA sequencing, and preclinical tumor models—we demonstrate the efficacy of this combination in overcoming drug resistance and enhancing anti-tumor immunity.Kinetic analyses revealed that CDK7i primarily suppresses RNA polymerase II-mediated transcription, a key driver of CDK4/6i resistance. Mechanistically, CDK7i prevents E2F activity amplification following retinoblastoma protein (Rb) degradation, a critical step in the development of resistance. Consequently, combining CDK4/6i and CDK7i synergistically suppresses E2F-driven transcriptional programs, resulting in robust inhibition of tumor proliferation in both HR+ and TNBC models.In vivo studies using syngeneic and patient-derived xenograft organoid models showed that this combination therapy not only suppresses tumor growth but also reprograms the tumor microenvironment (TME). RNA sequencing of treated tumors revealed upregulation of immune response pathways, including IFN-γ and TNF-α signaling, and increased expression of cytokines such as Cxcl9, Cxcl10, and Ciita. Flow cytometry and immunohistochemistry further confirmed enhanced infiltration of CD8+ T cells and natural killer cells into the TME, accompanied by a reduction in immunosuppressive macrophages. These changes collectively amplify anti-tumor immunity, providing an additional therapeutic benefit.This dual CDK4/6 and CDK7 inhibition approach represents a promising first-line strategy for TNBC and a second-line option for HR+ breast cancer resistant to CDK4/6i and endocrine therapy. These findings not only provide a strong rationale for advancing CDK7i into clinical trials but also highlight the therapeutic potential of targeting transcriptional regulation to overcome resistance in breast cancer. Citation Format: Sungsoo Kim, Eugene Son, Haram Park, Minah Kim, Hee Won Yang. Dual CDK4/6 and CDK7 inhibition: A synergistic strategy to overcome resistance and enhance anti-tumor immunity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 426.