title: Co-treatment of LY294002 or MK-2206 with AZD5363 Attenuates AZD5363-induced Increase in the Level of Phosphorylated AKT.
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.
authors: Research Institute, National Cancer Center, Goyang-si, Republic of Korea.
authors: Ae-Ran
authors: AR
authors: Choi
authors: Research Institute, National Cancer Center, Goyang-si, Republic of Korea.
authors: Ju-Hwa
authors: JH
authors: Kim
authors: Research Institute, National Cancer Center, Goyang-si, Republic of Korea.
authors: Yeon Hwa
authors: YH
authors: Woo
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors: Ji Hyun
authors: JH
authors: Cheon
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea hkims@skku.edu syoon88@gmail.com.
authors: Hyung Sik
authors: HS
authors: Kim
authors: Research Institute, National Cancer Center, Goyang-si, Republic of Korea hkims@skku.edu syoon88@gmail.com.|School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors: Sungpil
authors: S
authors: Yoon
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002867:Chromones; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D009025:Morpholines; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D009025:Morpholines; D011743:Pyrimidines; D011758:Pyrroles; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; C575618:capivasertib
keywords: AZD5363; LY294002; MK-2206; PI3K/AKT/mTOR; pAkt