Abstract P4-12-20: OKI-219 enhances activity of SOC therapies in double and triple combinations in pre-clinical PI3Kα H1047R mutant breast cancer models

作者：Molly A. Taylor, Maria Hoh, Qian Zhao, David A. Mareska, Mark L. Boys, Yevgeniy Izrayelit, Richard Woessner, Duncan Walker, James D. Winkler, Sam Agresta · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1557-3265.sabcs24-p4-12-20 · 研究领域：Advanced Breast Cancer Therapies

Abstract Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are found in approximately 15% of breast cancers and lead to constitutive activation of the PI3K/AKT/mTOR signaling pathway. Targeting PI3Kα in cancer is a therapeutically proven strategy, with the approved drug alpelisib showing clinical activity alone and in combination with other therapies. However, non-mutant selective inhibitors of PI3Kα are associated with significant toxicities, such as hyperglycemia, rash, and diarrhea, due to on-target inhibition of the wild-type enzyme. OKI-219 is an orally bioavailable and brain penetrant PI3KαH1047R mutant-selective inhibitor with greater than 100-fold selectivity for the H1047R mutation over wild-type PI3Kα. We have previously demonstrated that OKI-219 shows robust antitumor activity both as a single agent and in combination with SERDs or HER2-targeted agents in models of PI3KαH1047R-mutated cancer. Notably in these studies, no changes in insulin or glucose are observed, supporting the potential for OKI-219 to achieve therapeutically active exposures in the absence of on-target toxicity. CDK4/6 inhibitors in combination with ER-targeted agents are a mainstay of the treatment of HR+ breast cancer, where activation of PI3Kα signaling is associated with a poorer outcome. We investigated the impact of combining OKI-219 with CDK4/6 inhibitors and endocrine agents in PI3KαH1047R-mutated models. In vitro, in the T47D ER+, PI3KαH1047R model, the combination activity of OKI...