VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim

// Nurulhuda Mustafa 1 , Jeannie Xue Ting Lee 2 , Huey Fang Adina Nee 2 , Chonglei Bi 1 , Tae-Hoon Chung 2 , Stefan Hart 4 and Wee Joo Chng 1, 2, 3 1 Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore 3 Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore 4 S*BIO Pte Ltd., Singapore Correspondence to: Wee Joo Chng, email: mdccwj@nus.edu.sg Keywords: myeloma, dual PI3K/mTOR inhibitor, RARRES3, panobinostat, therapeutics Received: March 28, 2017 Accepted: September 22, 2017 Published: October 20, 2017 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.