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VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim. (Oncotarget, Oct 2017)

Mustafa N1, Ting Lee JX2, Adina Nee HF2, Bi C1, Chung TH2, Hart S3, Chng WJ1,2,4

Author information
1 Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
3 SBIO Pte Ltd., Singapore.
4 Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.

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.

KEYWORDS: RARRES3; dual PI3K/mTOR inhibitor; myeloma; panobinostat; therapeutics

PMID: 29254208