1. Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma
- Author
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Gabriel De Avila, Steven A. Eschrich, Ariosto S. Silva, Min Liu, David C. Koomen, Mark B. Meads, Timothy J. Garrett, Oliver A. Hampton, Taiga Nishihori, Raghunandan Reddy Alugubelli, Alexandre Tungesvik, Kenneth H. Shain, Dario M. Magaletti, Bin Fang, Paula Oliveira, Zhijie Jiang, Eric A. Welsh, John M. Koomen, Laurel E. Meke, and Joy Guingab-Cagmat
- Subjects
0301 basic medicine ,Melphalan ,Purine ,Metabolite ,Transplantation, Autologous ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Metabolomics ,medicine ,Humans ,Purine metabolism ,Multiple myeloma ,030102 biochemistry & molecular biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,General Chemistry ,medicine.disease ,Transplantation ,030104 developmental biology ,chemistry ,Cancer research ,Multiple Myeloma ,business ,Drug metabolism ,medicine.drug - Abstract
Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge. Here, we describe a proteometabolomic approach to examine mechanisms of acquired melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP, data available at PRIDE: PXD019725), acute-treatment metabolomics, and western blot analyses have allowed us to further elucidate metabolic processes associated with melphalan resistance. Proteometabolomic data indicate that drug-resistant cells have higher levels of pentose phosphate pathway metabolites. Purine, pyrimidine, and glutathione metabolisms were commonly altered, and cell-line-specific changes in metabolite levels were observed, which could be linked to the differences in steady-state metabolism of naïve cells. Inhibition of selected enzymes in purine synthesis and pentose phosphate pathways was evaluated to determine their potential to improve melphalan's efficacy. The clinical relevance of these proteometabolomic leads was confirmed by comparison of tumor cell transcriptomes from newly diagnosed MM patients and patients with relapsed disease after treatment with high-dose melphalan and autologous stem-cell transplantation. The observation of common and cell-line-specific changes in metabolite levels suggests that omic approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the use of high-dose melphalan.
- Published
- 2021