Methylthioadenosine phosphorylase (MTAP) is an enzyme responsible for processing a specific cellular byproduct, and its loss has emerged as a significant genetic event in the landscape of cancer. This gene is absent in approximately 15% of all human cancers, a deletion that leaves the tumor cells with a profound metabolic defect. While this loss is initially a disadvantage for the cell, it paradoxically creates a unique and exploitable vulnerability. Researchers are now working to leverage this metabolic weakness, turning the cancer cell’s own deficiency into a highly selective target for new precision therapies.
The Role of MTAP in Cellular Metabolism
The MTAP enzyme functions as a recycler, playing a specific part in the methionine salvage pathway, a process that helps cells conserve resources. Methionine is an amino acid that becomes S-adenosylmethionine (SAM), the cell’s primary methyl group donor. After SAM donates its methyl group, it is converted into a molecule called Methylthioadenosine, or MTA.
Healthy cells rely on MTAP to rapidly break down the MTA byproduct. MTAP cleaves MTA into two reusable components: adenine, which supports the cell’s purine nucleotide pool, and 5-methylthioribose-1-phosphate, which is recycled to regenerate methionine. This salvage function ensures the cell maintains a steady supply of necessary components for growth and division.
The Genetic Connection to Cancer
The reason for MTAP loss in cancer lies in a genetic accident of proximity on a specific chromosome. The MTAP gene is located on the short arm of chromosome 9, at position 9p21. This region contains one of the most frequently deleted segments in human malignancies.
Crucially, the MTAP gene sits very close to the CDKN2A gene, a major tumor suppressor that encodes the p16 protein. The p16 protein acts like a brake on cell division, and its loss is a common driver of cancer growth. Because the two genes are located only about 100,000 base pairs apart, the large-scale deletion that removes the CDKN2A tumor suppressor almost always co-deletes the MTAP gene.
The co-deletion of MTAP alongside CDKN2A is common in several aggressive cancers, including glioblastoma, pancreatic cancer, melanoma, and non-small cell lung cancer. In some tumor types, the frequency of this simultaneous loss can be as high as 80% to 90% of cases. This event is considered a “passenger deletion” because the primary benefit to the cancer cell is the loss of CDKN2A, while the loss of MTAP is collateral damage.
Creating a Metabolic Weakness
The functional consequence of losing the MTAP enzyme is the buildup of its substrate, Methylthioadenosine (MTA), inside the cell. MTA accumulates to high concentrations, acting as an internal metabolic disruptor. This accumulation creates a unique state of cellular stress not present in healthy cells, which efficiently process MTA.
The accumulated MTA acts as a selective inhibitor of a different enzyme called Protein Arginine Methyltransferase 5 (PRMT5). PRMT5 is a regulatory enzyme that adds methyl groups to various proteins, controlling processes like gene expression and cell cycle progression. MTA accumulation partially inhibits PRMT5, reducing its basal activity.
This reduced activity puts the cancer cell into a precarious “hypomorphic” state where its PRMT5 function is already compromised. The cancer cell has adapted to survive with this low-level inhibition, but it becomes hypersensitive to any further reduction in PRMT5 activity.
Exploiting MTAP Loss for Targeted Treatment
The strategy to attack MTAP-deficient cancer cells is based on the concept of synthetic lethality. This describes a relationship where the loss of either of two pathways alone is survivable, but the simultaneous loss of both is lethal. In MTAP-deleted tumors, the loss of MTAP is the first hit, and researchers seek a drug to deliver the second, fatal hit.
One primary approach focuses on fully inhibiting the PRMT5 enzyme, which is already partially suppressed by accumulated MTA. Small-molecule PRMT5 inhibitors are designed to push the weakened PRMT5 activity past a tolerable threshold, causing MTAP-deleted cells to die while sparing healthy cells. Normal cells, which have intact MTAP and low MTA levels, can tolerate the drug’s partial inhibition of PRMT5 activity. Several next-generation PRMT5 inhibitors are currently in clinical trials, aiming to leverage this selectivity.
Another therapeutic strategy targets the purine salvage pathway, which MTAP also supports. Since MTAP-deficient cells cannot recycle adenine, they become dependent on the de novo synthesis pathway to create new purines, the building blocks of DNA and RNA. Drugs that inhibit this de novo purine synthesis pathway, such as the antifolate chemotherapy agent pemetrexed, have shown increased effectiveness in patients whose tumors harbor the MTAP deletion.