| Abstract: |
Recent phase 3 clinical trial showed improved radiographic progression-free survival in PTEN-deficient prostate cancers treated with combined Akt and AR inhibition. Building on this and our previous research into PI3K and AR signaling interactions, we aimed to define the mechanisms of response and resistance to Akt inhibition. We discovered that restoration of mTOR signaling was the early dominant driver of resistance to Akt inhibition. Mechanistically, this can be achieved through molecular alterations, resulting in loss of negative regulators of mTOR. Unexpectedly, we discovered that this was dominated by restoration of mTOR signaling through the nutrient sensing arm. This can be achieved by loss of the components of the GATOR/KICSTOR complexes or through cellular processes, leading to the recycling of amino acids. The addition of an mTOR inhibitor restored sensitivity to Akt inhibition and represents a precision-based strategy to overcome resistance in the clinic. Copyright © 2025 The Authors, some rights reserved; |
| Keywords: |
signal transduction; protein kinase b; genetics; clinical trial; mouse; animal; metabolism; animals; mice; progression free survival; protein kinase inhibitor; drug effect; drug resistance; pathology; drug resistance, neoplasm; cell line, tumor; protein kinase inhibitors; prostatic neoplasms; prostate tumor; tumor cell line; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; pten phosphohydrolase; urology; amino acids; drug therapy; mammalian target of rapamycin inhibitor; mtor signaling; pten protein, human; prostate cancers; tor serine-threonine kinases; target of rapamycin kinase; amino-acids; mtor inhibitors; cellular process; restoration; mtor protein, human; humans; human; male; negative regulators; energy efficiency; sensing arm; signaling interactions; uncouplings
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