Co-treatment of LY294002 or MK-2206 with AZD5363 Attenuates AZD5363-induced Increase in the Level of Phosphorylated AKT

Anticancer Res. 2016 Nov;36(11):5849-5858. doi: 10.21873/anticanres.11170.

Abstract

Clinical trials are in progress on AZD5363, an inhibitor of protein kinase B (AKT), to assess its effects on the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Cells treated with AKT inhibitors have been reported to activate alternative pathways in order to escape growth inhibition. AZD5363-sensitized Hs578T breast cancer cells displayed reduced levels of phosphorylated glycogen synthase kinase 3 beta (pGSK3β). Interestingly, in AZD5363-treated cells, the level of phosphorylated (activated) AKT (pAKT) increased. Since pAKT positively correlates with cancer growth and survival, we aimed to identify conditions that could reduce AZD5363-induction of pAKT. We examined whether AZD5363 induction of pAKT could be reduced by co-treatment with inhibitors of the PI3K/AKT/mTOR pathway (LY294002, MK-2206, wortmannin, perifosine, rapamycin, everolimus, and temsirolimus). We observed that co-treatment of LY294002 or MK-2206 with AZD5363 reduced the level of pAKT. Since MK-2206 is clinically used, we propose that co-treatment using MK-2206 with AZD5363 would prove beneficial in blocking the AZD5363-induced pAKT signaling pathway. Our findings contribute to the development of AZD5363-based sensitization therapies for patients with cancer.

Keywords: AZD5363; LY294002; MK-2206; PI3K/AKT/mTOR; pAkt.

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Chromones
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Morpholines
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*

Substances

  • Chromones
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • Morpholines
  • Pyrimidines
  • Pyrroles
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Proto-Oncogene Proteins c-akt
  • capivasertib