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.
Highlights
The malignant proliferation and pathophysiology of multiple myeloma (MM) cells is driven by genetic aberrations in the cell and sustained by the rich signaling input derived from the interaction between the myeloma cells and the bone marrow microenvironment (BMM)
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
Western blot analysis confirms the dual inhibitory activity of VS-5584. It showed that the protein levels of the substrates of (1) the PI3K pathway- phospho-Akt (Thr308) and phosphoGSKβ as well as substrate of (2) the mTORC2 pathway phospho-Akt (Ser473) and (3) mTOR/AKT substrate, phospho-S6 have been attenuated by VS5584 treatment
Summary
The malignant proliferation and pathophysiology of multiple myeloma (MM) cells is driven by genetic aberrations in the cell and sustained by the rich signaling input derived from the interaction between the myeloma cells and the bone marrow microenvironment (BMM). The PI3K/Akt/ mTOR pathway is central to this complex signaling network and can be found constitutively active in MM cell lines as well as bone marrow biopsies of MM patients [1] It is the major pathway stimulated by bone marrow growth factor cytokines IL-6 and IGF-1 and has been shown to play a key role in mediating MM proliferation, survival and cell death [1, 2]. The authors reported that by targeting the mir-451-mediated activation of the PI3K/mTOR/Akt pathway with inhibitors Rapamycin and S14161, the myeloma CSC population was directly reduced via apoptosis [4]. Taken together, these evidence demonstrate the potential for inhibiting the PI3K/mTOR/Akt pathway for the effective and persistent retardation and prevention of in vivo growth of MM
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