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Title: VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim
Authors: Mustafa, N 
Ting Lee, J.X 
Adina Nee, H.F 
Bi, C
Chung, T.-H 
Hart, S
Chng, W.J 
Keywords: 5 (9 isopropyl 8 methyl 2 morpholino 9h purin 6 yl) 2 pyrimidinamine
beta catenin
BIM protein
caspase 3
cyclin D2
cyclin dependent kinase 4
cytochrome c
dickkopf 1 protein
mammalian target of rapamycin
messenger RNA
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
phosphatidylinositol 3 kinase
protein Bax
protein bcl xl
protein kinase B
protein S6
Akt signaling
animal experiment
animal model
antineoplastic activity
cancer inhibition
cell viability
cellular distribution
concentration response
controlled study
down regulation
drug cytotoxicity
drug effect
drug efficacy
drug mechanism
drug potentiation
enzyme activation
enzyme activity
G1 phase cell cycle checkpoint
gene expression profiling
gene expression regulation
gene silencing
human cell
in vivo study
multiple myeloma
multiple myeloma cell line
protein cleavage
protein expression
protein phosphorylation
RARRES3 gene
therapeutic index
tumor suppressor gene
tumor volume
tumor xenograft
Issue Date: 2017
Citation: Mustafa, N, Ting Lee, J.X, Adina Nee, H.F, Bi, C, Chung, T.-H, Hart, S, Chng, W.J (2017). VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim. Oncotarget 8 (60) : 101847-101864. ScholarBank@NUS Repository.
Abstract: The PI3K/mTOR/AKT pathway is an integral regulator of survival and drug resistance in multiple myeloma (MM). VS-5584 was synthesized with dual-specific and equipotent activity against mTORC1/2 and all four Class I PI3K isoforms so as to durably inhibit this pathway. We show that VS-5584 is highly efficacious against MM cell lines even in the presence of IL-6 and IGF-1 and that this growth inhibition is partially dependent on Bim. Importantly, VS-5584 triggers apoptosis in patient cells with a favorable therapeutic index. Gene expression profiling revealed a VS-5584-induced upregulation of RARRES3, a class II tumor suppressor gene. MM patient databases, UAMS and APEX, show that RARRES3 is under-expressed in 11q13 subsets which correlates with the reduced effectiveness of VS-5584 in 11q13 cell lines. Silencing RARRES3 expression significantly rescues VS-5584-induced cell death and increases cyclin D2 expression but not cyclin D1 or other cyclins implying a role for RARRES3 in cell cycle arrest. In vivo, VS-5584 significantly reduces the tumor burden of MM mouse xenografts. We further identified that VS-5584 synergised with Dexamethasone, Velcade, and exceptionally so with HDAC inhibitor, Panobinostat. Interestingly, this was consistently observed in several patient samples, proposing a promising novel clinical strategy for combination treatment especially in relapsed/refractory patients. © Mustafa et al.
Source Title: Oncotarget
ISSN: 19492553
DOI: 10.18632/oncotarget.21988
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