The therapeutic potential of targeting the metabolic enzyme MAT2A in multiple myeloma

Multiple myeloma (MM) is the second most prevalent hematological malignancy characterized by clonal expansion of malignant plasma cells within the bone marrow. Despite considerable progress in treatment approaches, MM remains incurable, primarily due to the inevitable development of multi-drug resistance. Thus, therapies capable of inducing durable elimination of MM cells are urgently needed. Emerging evidence supports the involvement of epigenetic defects in MM cell drug resistance. Several approaches for reprograming these defects have been investigated, mainly focusing on DNA and histone methylation. Preclinical results were shown to be promising, yet clinical results were only modest or often associated with major toxicity when used in combination with the standard of care agents. Therefore, there is a need to better understand the involvement of the different methylation processes in MM progression and relapse and to develop more efficient strategies to target them. In this dissertation, we propose that methionine adenosyltransferase 2α (MAT2A), the primary producer of the methyl donor S-adenosylmethionine (SAM), represents a novel therapeutic target in MM.

To address this, we first explored the impact of MAT2A inhibition on MM cell functionality (Chapter III). We found that MAT2A inhibition using either genetic inhibition or the small molecule inhibitor FIDAS-5 led to a reduction in intracellular SAM levels, which resulted in impaired MM cell viability and proliferation and induction of apoptosis. Mechanistically, MAT2A inhibition inactivated the mTOR-4EBP1 pathway, correlating with a clear decrease in global protein synthesis. MAT2A targeting with FIDAS-5 was also able to reduce tumor burden in the murine 5TGM1 model significantly. Finally, MAT2A inhibition sensitized MM cells to the standard-of-care agent bortezomib in both primary human CD138+ MM cells and MM cell lines. These findings demonstrate the potential of MAT2A as a novel therapeutic target in MM. Given MAT2A's key role in the biosynthesis of SAM, the primary methyl-donor for all methylation processes, we next explored its role in the epigenetic landscape of MM (Chapter IV), focusing mainly on DNA and histone methylation. Genetic depletion of MAT2A led to a pronounced decrease in global DNA methylation levels and significant reduction in several repressive histone methylation marks (H3K27me3 and H3K9me2). Through transcriptome analysis, we identified that MAT2A mainly regulates expression of genes involved in pathways crucial for cell cycle progression and cell survival in MM. Moreover, by combining the methylation sequencing data with the RNA-seq data, we identified twenty methylation-regulated differently expressed genes, including OLFM1, ADAM11, CASZ1 and JAK3, upon MAT2A depletion. Finally, a diminished DNA damage response was observed upon MAT2A inhibition, providing the rational for combining the MAT2A inhibitor AG-270 with compounds inducing DNA damage or targeting DNA repair in MM.

In conclusion, this dissertation uncovers for the first time the role and therapeutic potential of the metabolic enzyme MAT2A in MM. Our findings highlight the role of MAT2A in remodeling the epigenetic landscape in MM cells and reveal the underlying mechanisms of the anti-MM effects of MAT2A inhibition. Moreover, our preclinical results provide new perspectives for MM combination strategies.