Abstract C084: Metabolomic profiling identifies molecular modifiers contributing to proteasome inhibitor resistance in multiple myeloma

Abstract

Abstract Metabolic reprogramming plays a crucial role in the maintenance and differentiation of various cancers, including multiple myeloma (MM), the second-most common incurable hematological malignancy. Drug resistance poses a significant challenge to conventional proteasome inhibitor (PI) based therapy. A body of literature suggests that several metabolites are significantly deregulated in MM patients, however, their role in driving resistance is unclear. This study aims to identify metabolites modulated during acquired resistance to proteasome inhibitors in relapsed refractory (RR)MM. Two clinically relevant cell line models of PI-resistance (PIR) were developed by dose-escalation of the PI over one year. Cell cytotoxicity assays, immunoblotting, immunofluorescence, and flow cytometric analyses were used to assess the resistance phenotype. Mass spectrometry-based metabolomic profiling was performed to identify altered metabolites in resistant as compared to sensitive cell lines. PIR cells demonstrated pan-resistance to multiple PIs, including a >10-fold increase in IC50 for oprozomib compared to parental cells. PIR cells had higher bioenergetic and glycolytic activity (Seahorse) while gene expression profiling suggested downregulation of oxidative phosphorylation. Mass spectrometry-based metabolomic profiling identified distinct metabolites deregulated in drug-resistant cells. The metabolomic profiles of the drug-resistant cell lines showed that the lipid synthesis and beta-oxidation of fatty acid pathways were highly modulated. Several pathway components demonstrated a negative association with overall survival in multiple myeloma patient datasets (MMRF, GSE31161 & GSE9782). PI resistance led to increased phosphorylation of ACLY involved in fatty acid synthesis and increased expression of CPT1A indicative of activation of the beta-oxidation pathway. Use of ACLY and FASN tool compounds affected proliferation, survival, and response to treatment in PIR cells. Metabolites modulated during acquired resistance to proteasome inhibitor in relapsed refractory (RR)MM were identified and potential mechanisms driving resistance were studied. Citation Format: Snehal M Gaikwad, Vincent Keith Hughitt, Nana Gyabaah-Kessie, Mikaela Matera-Vatnick, Aleksandra A Michalowski, Anaisa Quintanilla-Arteaga, Thorkell Andresson, Beverly A Mock. Metabolomic profiling identifies molecular modifiers contributing to proteasome inhibitor resistance in multiple myeloma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C084.