title: PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242.
abstract: A deeper understanding of the complex pathogenesis of multiple myeloma (MM) continues to lead to novel therapeutic approaches. Prior studies suggest that 3-phosphoinositide-dependent kinase 1 (PDK1) is expressed and active, acting as a crucial regulator of molecules that are essential for myelomagenesis. In the present study, we show that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1, induces potent cytotoxicity in MM cell lines including Dexamethasone-resistant cell line, but not in human normal cells. Insulin-like growth factor-1 could not rescue GSK-470-induced cell death. Moreover, GSK-470 down-modulates phosphor-PDK1, thereby inhibiting downstream phosphor-AKT at Thr308 and mTOR complex 1 (mTORC1) activity. However, GSK-470 could not affect mTORC2 activity and phosphor-AKT at Ser473. RPMI 8226 and OPM-2 cells with low expression of PTEN show relative resistant to GSK-470. Knockout of PTEN by shRNA resulted in a partial reversion of GSK-470-mediated growth inhibition, whereas overexpression of PTEN enhanced myeloma cell sensitivity to GSK-470, suggesting that the sensitivity to GSK-470 is correlated with PTEN expression statue in MM cells. Combining PP242, a dual mTORC1/C2 inhibitor, with GSK-470, had greater antimyeloma activity than either one alone in vitro and in MM xenograft model established in immunodeficient mice. In particular, this combination was able to result in a complete inhibition of mTORC1/C2 and full activity of AKT. Together, these findings raise the possibility that combining PDK1 antagonist GSK-470 with mTORC1/C2 inhibitors may represent a novel strategy against MM including drug-resistant myeloma, regardless of PTEN expression status.
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Xianbo
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Jueying
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Liangshun
authors.initials: L
authors.lastname: You
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Qian
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011687:Purines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C555257:GSK 2334470; D007191:Indazoles; D007211:Indoles; D011687:Purines; D011743:Pyrimidines; D064413:3-Phosphoinositide-Dependent Protein Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; C578562:PDPK1 protein, human; C572919:PP242
keywords: PDK1; PTEN; mTOR; multiple myeloma