Work

Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy

Year: 2025

Type: article

Abstract: The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal target in cancer treatment, driving substantial investigation into PI3K inhibitors (PI3Ki). However, the common on-target adverse effect of hyperglycemia presents a substantial challenge to their clinical application. There is an urgent need to discover an anti-hyperglycemic agent that maintains the efficacy of PI3Ki. We conducted a comprehensive study to explore the interaction between exogenous hyperinsulinemia and PI3Ki in SKOV3 and OVCAR3 ovarian cancer cell lines. We used Western blotting, CCK-8, and EdU assays to determine the effect of this interaction on cell proliferation. In addition, we evaluated the anti-hyperglycemic effects of dorzagliatin in a PI3Ki-induced hyperglycemic mice model. Cell line-derived xenograft (CDX) models were employed to evaluate the in vivo tumor growth inhibitory effects of combining dorzagliatin with PI3Ki. Western blot analysis demonstrated that insulin activated the AKT/INSR/mTOR pathway, reversing PI3Ki-induced p-AKT inhibition. Insulin also attenuated the anti-proliferative effects of PI3Ki. In the hyperglycemic mouse model, dorzagliatin significantly reduced blood glucose levels compared to controls. The combination therapy group (Dorzagliatin + PI3Ki) in CDX models showed a marked reduction in tumor volume. Dorzagliatin not only mitigated hyperglycemia but also enhanced the anti-tumor effects of PI3Ki. A clinical trial (NCT06117566) in cervical cancer patients supported these findings, showing that dorzagliatin stabilized blood glucose levels, facilitated body weight recovery, and achieved a confirmed partial response (PR). Dorzagliatin shows promise for managing PI3Ki-associated hyperglycemia, thereby enhancing its therapeutic efficacy. The activation of liver glycogen kinase and insulin regulation may be key mechanisms underlying its therapeutic benefits. • Insulin has been shown to diminish the antitumor activity of PI3Ki in SKOV3 and OVCAR3 cell lines. • Dorzagliatin is capable of reducing PI3Ki-induced hyperglycemia and hyperinsulinaemia in BALB/c mice. It significantly augments the anticancer effects of PI3Ki in CDX models and attenuates HK-2 activity. • A clinical case further corroborates that dorzagliatin can mitigate PI3Ki-induced hyperglycemia and ultimately lead to a confirmed partial response.

Source: Molecular Metabolism

DOI: 10.1016/j.molmet.2025.102151