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

Autor:	Walker ZJ; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Idler BM; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Davis LN; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Stevens BM; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., VanWyngarden MJ; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Ohlstrom D; Biomedical Sciences and Biotechnology, Graduate School, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Bearrows SC; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Hammes A; Center for Innovative Design and Analysis, Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Smith CA; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Jordan CT; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Mark TM; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Forsberg PA; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Sherbenou DW; Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. daniel.sherbenou@ucdenver.edu.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Feb 01; Vol. 27 (3), pp. 819-830. Date of Electronic Publication: 2020 Oct 27.
DOI:	10.1158/1078-0432.CCR-20-2246
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu