Adaptive mitochondrial reprogramming and resistance to PI3K therapy.

Area of Science:

• Oncology
• Molecular Biology
• Mitochondrial Biology

Background:

• Small molecule inhibitors targeting phosphatidylinositol-3 kinase (PI3K) are developed for cancer therapy.
• Clinical efficacy of PI3K inhibitors is limited by resistance mechanisms.

Purpose of the Study:

• To investigate PI3K therapy-induced tumor reprogramming and resistance mechanisms.
• To identify novel combination therapies to overcome PI3K inhibitor resistance.

Main Methods:

• Studied PI3K therapy effects in patient-derived tumor organoids, GBM cell lines, and an intracranial GBM mouse model.
• Investigated mechanisms of resistance using metabolomics, mitochondrial bioenergetics, and phosphoproteomics.
• Performed high-throughput drug screening to identify synergistic combination therapies.

Main Results:

• PI3K therapy induced metabolic reprogramming and recruited Akt2 to mitochondria, phosphorylating cyclophilin D (CypD).
• Mitochondrial Akt2-phosphorylated CypD enhanced mitochondrial bioenergetics and conferred resistance to PI3K therapy.
• Combination of PI3K inhibitors with Gamitrinib (CypD antagonist) induced synergistic anticancer activity and improved survival in a GBM model.

Conclusions:

• PI3K antagonists can promote drug resistance by hijacking mitochondrial functions for tumor survival.
• Targeting mitochondrial adaptation in combination with PI3K inhibitors offers a promising strategy to enhance cancer therapy efficacy.