Abstract 7135: A first-in-class orally bioavailable small molecule to overcome treatment resistance in hormone receptor-positive breast cancer

Abstract CDK4/6 inhibitors combined with antiestrogens such as fulvestrant represent frontline therapy for hormone receptor-positive (HR+) breast cancer; however, therapeutic resistance inevitably emerges in a substantial subset of patients through diverse molecular mechanisms. To address this challenge, we developed PMG-A9, a novel, orally bioavailable small molecule designed to restore the function of a key tumor suppressor frequently inactivated across cancers. PMG-A9 potently downregulates major resistance drivers, including Cyclin D1 and c-Myc, in a dose-dependent manner at sub-nanomolar concentrations, while upregulating cell-cycle inhibitors and pro-apoptotic proteins, demonstrating its potential to overcome resistance to CDK4/6 inhibitors and/or fulvestrant. In preclinical HR+ breast cancer xenograft models, PMG-A9 exhibits robust single-agent antitumor activity and pronounced synergy when combined with these agents. These findings highlight tumor-suppressor reactivation as a promising and broadly applicable therapeutic strategy with the potential to address resistance not only in HR+ breast cancer but also across a wide range of tumor types. Citation Format: Hee-Sung Park, Chakrapani Subramanyam, Kyu-kwang Cho, Se Hee Hyun, Yeonjee Kahm. A first-in-class orally bioavailable small molecule to overcome treatment resistance in hormone receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7135.