Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy

Abstract

Purpose:The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell maturation antigen–specific chimeric antigen receptor T-cell therapies provide only a temporary benefit before patients succumb to their disease. In this article, we interrogate the unique sensitivity of multiple myeloma cells to the alternative strategy of blocking protein translation with omacetaxine.Experimental Design:We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary multiple myeloma patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis.Results:Almost universally, primary patient multiple myeloma cells exhibit >2.5-fold increased rates of protein translation compared with normal marrow cells. Ex vivo treatment with omacetaxine resulted in >50% reduction in viable multiple myeloma cells. In this cohort, high levels of translation serve as a biomarker for patient multiple myeloma cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in multiple myeloma cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment resensitized the multiple myeloma cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to multiple myeloma survival.Conclusions:Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory multiple myeloma.

Targeting the ribosome to treat multiple myeloma

“… 55 , 56 Translational initiation inhibitors rocaglates and omacetaxine have been shown to suppress MM cell proliferation and induce cell death. 54 , 57 In line with these findings, we show that the combination of CX-5461 with panobinostat produced a double hit on ribosome biogenesis and mRNA translation in MM cells. Altogether, our findings support the feasibility of targeting the ribosome as an effective strategy to treat RRMM.…”

Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine Resistant Multiple Myeloma

“…These cell lines are referred to herein as H929-OR (Omacetaxine Resistant) and MM1S-OR. Previously, we found that baseline protein synthesis rate correlated with ex vivo omacetaxine response in primary MM samples (7). OP-puromycin staining of omacetaxine-resistant cells revealed a significant decrease in H929-OR cells, and an increase in a subpopulation of MM1S-OR (Supplemental Fig.…”

“…As drug combinations are more efficacious than single agents in the treatment of MM, development of new drug combinations is of particular interest, especially those that include multiple new agents that the malignant cells have not been exposed to previously. The protein synthesis inhibitor omacetaxine is a promising new backbone therapy that we have shown retains activity in multiply relapsed patients (7). The goal of this study was to better understand how MM cells respond to prolonged omacetaxine exposure and how future patients may develop resistance to this therapy.…”

“…A promising alternative approach to targeting protein homeostasis in multiple myeloma is through the blockade of protein synthesis. Previously, we and others showed that the mRNA translation inhibitor omacetaxine has potent and specific anti-myeloma activity in preclinical models, including primary samples from patients that had become proteasome inhibitor refractory (6, 7). Omacetaxine is FDA-approved for the treatment for chronic myeloid leukemia and has shown potential in other hematologic malignancies (8).…”

The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma

“…AKT-mediated sustained eIF4E expression and C/EBP translation have been proposed as the resistant mechanisms for IMiDs [ 61 ]. Moreover, the resistant mechanisms for current standard therapeutics for MM include aberrant MYC overexpression [ 50 ], and the increased rate of protein translation [ 62 ]. Considering these, one of the clinical positions of the dual-targeting therapy for RSK2 and AKT may be theoretically the salvage setting after treatment failure of PIs, and/or IMiDs with or without monoclonal antibodies for CD38 or SLAMF-7.…”