Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 04 2022
19 04 2022
Historique:
received:
15
06
2021
accepted:
25
03
2022
entrez:
20
4
2022
pubmed:
21
4
2022
medline:
22
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35440108
doi: 10.1038/s41467-022-29655-0
pii: 10.1038/s41467-022-29655-0
pmc: PMC9019088
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Adenosine Triphosphate
8L70Q75FXE
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2057Informations de copyright
© 2022. The Author(s).
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