SGLT2 inhibition improves PI3Kα inhibitor–induced hyperglycemia: findings from preclinical animal models and from patients in the BYLieve and SOLAR-1 trials

作者：Manuel Ruíz Borrego, Yen‐Shen Lu, Felipe Reyes-Cosmelli, Yeon Hee Park, Toshinari Yamashita, Joanne Wing Yan Chiu, Mario Airoldi, Nicholas Turner, Luis Fein, Farhat Ghaznawi, Jyotika Singh, Kristyn Pantoja, Christian Schnell, Murat Akdere, Stephen Chia · 发表于：Breast Cancer Research and Treatment · 年份：2024 · DOI：10.1007/s10549-024-07405-8 · 被引用次数：7 · 研究领域：Metabolism, Diabetes, and Cancer、PI3K/AKT/mTOR signaling in cancer、Diabetes Treatment and Management

PURPOSE: Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2- advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor-associated hyperglycemia. METHODS: Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor-bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score-matched cohort not receiving SGLT2i (n = 74) in both trials. RESULTS: Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hypergl...