Transition state analogue of MTAP extends lifespan of APCMin/+ mice

This study explained about the mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5′-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5′-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth.

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FIG: The role of 5′-methylthioadenosine phosphorylase (MTAP) in the context of methionine metabolism and polyamine synthesis. MTAP catalyzes the phosphorolysis of 5′-methylthioadenosine (MTA) to form adenine and 5-methylthio-α-D-ribose 1-phosphate (MTR-1-P), which can be recycled to form ATP and methionine followed by conversion to S-adenosyl-L-methionine (SAM) by the MAT2A-catalyzed reaction. The S-methyl of SAM (red) is conserved in the MTA salvage reaction enabled by MTAP action. MTAP inhibitors interfere with MTA metabolism leading to elevated MTA concentration in cells and growth disruption.

Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP−/− cancer cell lines.

Firestone, R.S., Feng, M., Basu, I. et al. Transition state analogue of MTAP extends lifespan of APCMin/+ mice. Sci Rep 11, 8844 (2021). https://doi.org/10.1038/s41598-021-87734-6

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