Abstract 3028: Tumor suppressor activation: unlocking a novel path to overcome CDK4/6 inhibitor resistance in HR-positive breast cancer

Abstract Clinically approved CDK4/6 inhibitor drugs, though initially effective, often generate acquired resistance in HR-positive breast cancer, leading to 25-35% of patients becoming nonresponsive. A number of drivers for this resistance have been identified, including cyclin D1 upregulation. Herein, we present an innovative strategy to tackle this pressing challenge. We have developed a novel small molecule, PMG-A7, that activates a key tumor suppressor critical to maintaining cellular homeostasis and regulating the cell cycle. PMG-A7 induces a robust, dose-dependent reduction in resistance drivers, demonstrating efficacy at single-digit nanomolar concentrations. Further, PMG-A7 upregulates cell cycle inhibitors such as p27, effectively countering CDK4/6 inhibitor resistance. When used in combination with a CDK4/6 inhibitor, PMG-A7 significantly suppresses resistance mechanisms. These findings highlight tumor suppressor activation as a promising combination therapeutic strategy to help overcome drug resistance to CDK 4/6 inhibitors in the clinic. Citation Format: Hee-Sung Park, Kyu-Kwang Cho, Martin Pettersson, Chakrapani Subramanyam. Tumor suppressor activation: unlocking a novel path to overcome CDK4/6 inhibitor resistance in HR-positive 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 3028.