Therapeutic Potential of Prmt5 and Mat2A As Synthetic Lethal Targets In Mtap-Deficient Gbm Tumors

<p>Homozygous deletion of methylthioadenosine phosphorylase (<em>MTAP</em>) is a frequent genetic alteration found in approximately 15% of all human cancers, including glioblastoma, pancreatic cancer, mesothelioma, urothelial bladder carcinoma, and lung squamous cell carcinoma. MTAP is a critical metabolic enzyme in the methionine salvage pathway responsible for the breakdown of methylthioadenosine (MTA). As a result, <em>MTAP</em>-deleted cells cannot metabolize MTA, leading to the accumulation of MTA. High levels of MTA in <em>MTAP</em>-deleted cells partially inhibit the activity of protein arginine methyltransferase 5 (PRMT5), making these cells sensitive to PRMT5 and MAT2A inhibition. Although elevated levels of MTA <em>in vitro</em> define a promising actionable metabolic vulnerability, the clinical relevance relies on exhibiting significant MTA accumulation in human tumors. Here, we demonstrate that, unlike cells in culture, MTA levels in <em>MTAP-</em>deleted primary human GBM tumors are not significantly higher compared to <em>MTAP</em>-intact tumors. This discrepancy is due to the secretion of MTA into the extracellular environment and its subsequent metabolism by stromal cells expressing MTAP. We also have demonstrated that the presence of <em>MTAP</em>-intact cells near <em>MTAP</em>-deleted cancer cells attenuates their sensitivity to PRMT5-MTA complex inhibitors. Moreover, we have demonstrated that putrescine, a metabolite in the polyamine biosynthesis pathway, can stimulate MTA production, and enhance the efficacy of PRMT5 inhibitor treatment in <em>MTAP</em>-deleted cells across multiple tumor cell lines, even in the presence of <em>MTAP</em>-intact cells. In summary, our findings highlight the metabolic discrepancies between in vitro models and primary human tumors, the influence of stromal infiltration on the synthetic lethal relationship between <em>MTAP</em>-deletion and PRMT5 inhibition, and the potential of co-treatment with putrescine and PRMT5 inhibitors to enhance this therapeutic approach.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Barekatain, Yasaman
• <p>0000-0002-4454-1496</p>

Contributors dc:contributor

• Raghu Kalluri, M.D., Ph.D
• Florian Muller, Ph.D.
• Ronald DePinho, M.D.

• PRMT5
• MAT2A
• Synthetic lethality
• MTAP-deficiency
• Human GBM tumors
• Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1290

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2347