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- Title
Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.
- Authors
Savill, Kristin M. Zimmerman; Lee, Brian B.; Oeh, Jason; Lin, Jie; Lin, Eva; Chung, Wei-Jen; Young, Amy; Chen, Wennie; Miś, Monika; Mesh, Kathryn; Eastham, Jeffrey; Gnad, Florian; Jiang, Zhaoshi; Stawiski, Eric W.; Haley, Benjamin; Daemen, Anneleen; Wang, Xiaojing; Koeppen, Hartmut; Modrusan, Zora; Martin, Scott E.
- 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 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. How resistance to different classes of AKT inhibitors can emerge is unclear. Here, the authors show that resistance to allosteric inhibitors is mainly due to mutation of AKT1 while the ATP competitive resistance is driven by activation of PIM kinases in prostate cancer models.
- Subjects
ALLOSTERIC regulation; PROSTATE cancer; DRUG target; KINASES; CELLULAR signal transduction
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-29655-0