Abstract A033: Peptide-mediated targeting of the CDK4 chaperone network in kidney cancer

Abstract Cyclin-Dependent Kinase 4 (CDK4) is a pivotal regulator of cell cycle progression. Its role in controlling the G1 to S transition is crucial for normal cellular growth and proliferation. Cell cycle dysregulation and CDK4 hyperactivity is common in various cancers and leads to uncontrolled cell division in the most common type of kidney cancer, clear cell renal cell carcinoma (ccRCC). Previous work has shown that patient response to CDK4 inhibitors lacks durability and can result in acquired resistance, indicating that alternative targeting strategies may offer clinical benefit. Heat shock protein 90 (Hsp90) and Heat shock protein 70 (Hsp70) are integral components of the cellular chaperone network that cooperate to maintain the stability and activity of many proteins, termed ‘clients.’ CDK4 activity depends on these chaperones, and targeted chaperone inhibition compromises CDK4 activation. In preclinical models, inhibition of Hsp70 and Hsp90 shows strong synergy; however, broad-spectrum chaperone inhibition leads to a pro-survival stress response that blocks apoptosis. Therefore, we hypothesized that disrupting the specific CDK4:chaperone interaction will cause apoptosis in ccRCC without inducing the pro-survival response. We used computational modeling based on the cryo-EM structure of the CDK4:chaperone complex to identify CDK4 residues predicted to engage with Hsp70 and Hsp90. We then evaluated whether peptides derived from these contacting residues could specifically disrupt CDK4:chaperone interaction. Among the candidates, the CDK4-2 peptide was determined to bind both Hsp70 and Hsp90 with nanomolar affinity. In ccRCC cells, CDK4-2 suppressed downstream CDK4 signaling and induced apoptosis. This work identifies CDK4-2 as a first-in-class dual chaperone-binding molecule that disrupts CDK4 signaling and provides a foundation for the development of multi-target inhibitors capable of interfering with cancer-associated protein complexes. Citation Format: Sara Cayaban, Jennifer Heritz, Luca Torielli, Matteo castelli, Sarah Backe, Mark Woodford, Dimitra Bourboulia, Jason Gestwicki, Giorgio Colombo, Mehdi Mollapour. Peptide-mediated targeting of the CDK4 chaperone network in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A033.