Uncoupling of Akt and mTOR signaling drives resistance to Akt inhibition in PTEN loss prostate cancers

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.

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Publication Details

Journal
Science Advances
Published
2025-02-07
DOI
https://doi.org/10.1126/sciadv.adq3802
Citations
11
Primary Topic
PI3K/AKT/mTOR signaling in cancer
Type
article
Field-Weighted Citation Impact
8.87
Controls
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article

Uncoupling of Akt and mTOR signaling drives resistance to Akt inhibition in PTEN loss prostate cancers

Harmanpreet Kaur, Elisa de Stanchina, Zeda Zhang, Qing Chang et al.
11 citations
Science Advances
PI3K/AKT/mTOR signaling in cancer
8.87
article

Uncoupling of Akt and mTOR signaling drives resistance to Akt inhibition in PTEN loss prostate cancers

Harmanpreet Kaur, Elisa de Stanchina, Zeda Zhang, Qing Chang, Charles L. Sawyers, Sanjoy Mehta, Brett S. Carver, Jesse Barnes, Ralph Garippa, Nazifa Salsabeel, Dan Li, Yu Chen, Xiaoping Chen, Young Sun Lee, Ninghui Mao
article en
11 citations

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.

Science AdvancesVol. 11(6)
Memorial Sloan Kettering Cancer Center (US), Howard Hughes Medical Institute (US)
Good health and well-being
Openalex Percentile: Top 2%
PI3K/AKT/mTOR signaling in cancer
8.87
DOIOpen Access PDFOpenAlex
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