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

      Methylthio-DADMe-Immucillin-A (MTDIA) is an 86 pM transition state analogue of human 5¢-methylthioadenosine phosphorylase (MTAP). 5¢-Methylthioadenosine (MTA) 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, an inhibitor 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. APCMin/+ mouse lifespan nearly doubled when treated with an optimal daily oral dose of 20 mg/kg/day MTDIA. Oral MTDIA reduced tumor burden and markedly improved anemia. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated a >4-fold increase in levels of MTA, the MTAP substrate. In vitro experiments generated an MTDIA-resistant FaDu cell line in culture. Genomic analysis of resistant cells showing 4-fold gene amplification of the methionine adenosyl transferase (MAT2A) locus. We hypothesize that MTDIA exerts its anti-cancer effects by increasing cellular concentrations of MTA, inhibiting PRMT5-mediated histone methylation and intron splicing to slow cancer cell growth. Oral dosing of MTDIA may provide a monotherapy for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis. MTDIA causes a chemical knock-out of MTAP and may therefore also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in cancer cell lines.
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