Abstract LB422: Selective targeting of CDK2 using molecular glue degraders for the treatment of HR-positive/HER2-negative breast cancer
Authors: Sofia Gkountela, William Tahaney, Vasiliki Vafeiadou, Christelle Bianda, Liam Cheeseman, Ambika Singh, Anna Diesslin, Martin Schillo, Sophia Nguyen, Luca Moccia, Christopher King, Yimao Liu, Chao Quan, Bradley DeMarco, Laura Schwander, Vaik Strande, Jessica Alers, Rajiv Narayan, Dave Peck, Sarah Pessa, Samuel Gilberto, John Castle, Filip Janku, Sharon Townson, Markus Warmuth, Magnus Walter, Beatrice Ranieri, Ralph Tiedt, Nina Ilic Widlund
Journal: Cancer Research (2025)

Abstract Cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and cyclin dependent kinase 2 (CDK2) act in a coordinated fashion to phosphorylate and repress RB protein, effectively driving cell proliferation via E2F activation. Currently, CDK4/6 inhibitors in combination with endocrine therapy are considered the standard of care for the treatment of hormone-receptor (HR)-positive/HER2-negative breast cancer, but unfortunately most patients with metastatic disease ultimately progress. High CCNE1 expression is considered one of the underlying mechanisms of resistance to CDK4/6-inhibition, and other adaptations to chronic CDK4/6-inhibition that increase reliance on the CDK2 pathway to sustain RB-E2F signaling are also thought to reduce CDK4/6 inhibitor effectiveness. Based on this, we reason that, targeting CDK2 in conjunction with CDK4/6 inhibition can provide more sustained and durable responses in this difficult-to-treat patient population. To identify molecular glue degraders (MGDs) that selectively target CDK2, we used our MGD discovery engine QuEENTM. Through this platform that encompasses biochemical and cellular assays as well as in silico modelling, we identified and further optimized molecules that induce CRBN engagement to drive selective CDK2 degradation. Unlike CDK2 inhibitors, our CDK2 MGDs spare other proteins such as closely related CDKs and, attesting to their superior selectivity, inhibit cell proliferation in an RB-dependent manner. Furthermore, these MGDs induce robust downstream pathway suppression, as evidenced by downmodulation of RB phosphorylation and E2F-driven gene expression. When dosed orally in in vivo models of HR-positive/HER2-negative breast cancer, these compounds drive deep tumor regression in combination with CDK4/6 inhibitor or triple combination with endocrine therapy (fulvestrant), resulting in enhanced downstream pathway suppression compared to CDK4/6 inhibitor alone. Owing to their superior selectivity, we expect that a CDK2 MGDs will avoid dose-limiting toxicities associated with less selective CDK2 inhibitors. Hence, CDK2 MGDs provide novel means to target an inadequately drugged target, offering a unique angle for populations in desperate need of treatment options. Citation Format: Sofia Gkountela, William Tahaney, Vasiliki Vafeiadou, Christelle Bianda, Liam Cheeseman, Ambika Singh, Anna Diesslin, Martin Schillo, Sophia Nguyen, Luca Moccia, Christopher King, Yimao Liu, Chao Quan, Bradley DeMarco, Laura Schwander, Vaik Strande, Jessica Alers, Rajiv Narayan, Dave Peck, Sarah Pessa, Samuel Gilberto, John Castle, Filip Janku, Sharon Townson, Markus Warmuth, Magnus Walter, Beatrice Ranieri, Ralph Tiedt, Nina Ilic Widlund. Selective targeting of CDK2 using molecular glue degraders for the treatment of HR-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB422.