Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.

ABSTRACT: The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways includi

SUBMITTER: Savill KMZ 

PROVIDER: S-EPMC9019088 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature