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

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 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 were associated with acquired resistance to MK-2206, ipatasertib resistance was driven by compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance could be overcome by treatment with ipatasertib, while ipatasertib resistance could be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.