MTAP-MAT2A synthetic-lethality induced by transition state analogs

Methylthioadenosine phosphorylase (MTAP) uniquely recycles methylthioadenosine (MTA) in humans, maintaining near zero MTA concentrations. The discovery that MTAP-deleted (MTAP-/-) tumors are uniquely sensitive to co-deletion of MAT2A or PRMT5 has led to intense interest in targeting MAT2A and PRMT5, a new synthetic-lethal approach to cancer therapy. Over a dozen clinical trials with MAT2A and/or PRMT5 inhibitors target 15% of human tumors that are MTAP-/-. However, only 1% of colorectal cancers (CRC) are MTAP-/-, excluding CRC patients from all these trials, along with 85% of all cancer patients with MTAP+/+ tumors. Drugs targeting MAT2A and PRMT5 are effective only when MTA is elevated in MTAP-/- tumors, but pharmacological MTAP inhibition can convert MTAP+/+ tumors to the MTAP-/- phenotype. We developed MTAP transition state analog inhibitors with picomolar efficacy and their prodrugs to optimize pharmacodynamics. Our MTAP inhibitors are highly specific, non-toxic agents that recapitulate the MTAP-/- phenotype in otherwise isogenic cells. MTAP inhibitors mimic genetic inactivation of MTAP-/- tumors, increasing both systemic and tumor MTA levels. Efficacy of these inhibitors was demonstrated in in multiple systems, and synthetic lethality with MAT2A or PRMT5 inhibitors was demonstrated . Therefore, combined inhibition of MTAP with MAT2A or PRMT5 opens CRC patients and other MTAP+/+ patients to ongoing clinical trials by this synthetic-lethal therapy. The mechanism impinges on PRMT5 inhibition. PRMT5 uses S-adenosylmethionine (SAM) to methylate 60 or more downstream regulatory proteins linked to inhibition of cancer cell growth. MAT2A inhibitors block SAM synthesis. MTA is a powerful inhibitor of PRMT5 and current-generation PRMT5 inhibitors require elevated tumor MTA for efficacy. Thus, the synergy among MTAP, MAT2A and PRMT5 inhibitors, also provides potential for dose de-escalation for these drugs in clinical trials to minimize reported toxicity. We established MTAP inhibitor and prodrug efficacy in human CRC cell lines, CRC organoid cultures and PDX models, and in ApcMin/+ mice tumor growth. Simultaneously targeting MTAP with MAT2A or PRMT5 is synergistic in cell lines and human CRC organoids. Aim 1 investigates pharmacodynamics and toxicology of MTAP prodrugs, 2 lead prodrugs thus far identified. Aim 2 tests MTAP inhibitors as monotherapy and in synthetic lethality with MAT2A or PRMT5 inhibitors. This uses patient CRC organoids (PDOs) and xenografts (PDXs) representing populations from the Bronx N.Y, Columbia-Presbyterian, and MD Anderson Cancer Centers. All PDOs and PDXs are annotated for demographics and mutational profile, permitting potential identification of patient subsets in regard to efficacy. Aim 3 focuses on MTAP induction of a major increase in KISS1, an inhibitor of CRC metastasis and CRC cell apoptosis. Link of KISS1 expression with drug induced cell apoptosis in the PDO and PDX models is determined, and in organoids, genetically modulating KISS1 expression on drug induced apoptosis and invasive phenotype is determined. Alternatives and future directions are discussed. Project Number: 1R01CA300091-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: LEONARD AUGENLICHT (+2 co-PIs) | Institution: ALBERT EINSTEIN COLLEGE OF MEDICINE, BRONX, NY | Award Amount: $692,197 | Activity Code: R01 | Study Section: Drug Discovery and Molecular Pharmacology C Study Section[DMPC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11294877