Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma

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.