The deletion of the methylthioadenosine phosphorylase (MTAP) gene is one of the most frequent genetic alterations observed in human cancers. This loss fundamentally alters the cell’s internal chemistry, creating a unique metabolic landscape and introducing a vulnerability not present in healthy cells. By understanding and targeting the consequences of MTAP deletion, scientists aim to develop highly selective and effective therapies against aggressive tumors.
What is the MTAP Protein and its Function?
The MTAP protein (Methylthioadenosine phosphorylase) is an enzyme central to cellular recycling within the methionine salvage pathway. It catalyzes the first step in salvaging components from 5′-methylthioadenosine (MTA), a byproduct of polyamine synthesis necessary for cell growth and division. MTAP acts as a phosphorylase, breaking down MTA into adenine and 5-methylthioribose-1-phosphate.
The resulting adenine is channeled back into the purine pool, which is essential for synthesizing DNA and RNA. The 5-methylthioribose-1-phosphate is converted to produce methionine. MTAP’s function is to efficiently recover and recycle these materials, supporting the cell’s need for purines and methionine.
The Genetic Basis for MTAP Loss in Cancer
The common occurrence of MTAP deletion in tumors is due to its physical location on chromosome 9, at the 9p21 locus. This region is frequently lost in many cancers because it contains the tumor suppressor gene CDKN2A.
Since MTAP and CDKN2A are located immediately next to each other, a single large chromosomal deletion event often removes both genes simultaneously. This co-deletion means the loss of CDKN2A almost always results in the accompanying loss of the metabolic MTAP gene. MTAP deletion occurs in approximately 15% of all tumors.
Common MTAP-Deleted Cancers
Specific malignancies frequently harbor this co-deletion, including:
- Pancreatic cancer
- Non-small cell lung cancer
- Mesothelioma
- Glioblastoma
- Melanoma
Metabolic Shift Following MTAP Deletion
The absence of the MTAP enzyme triggers a profound metabolic change within the cancer cell. When MTAP is non-functional, it cannot break down its substrate, 5′-methylthioadenosine (MTA). This failure in the recycling process causes MTA to accumulate dramatically, sometimes reaching high intracellular levels within the MTAP-deleted cells.
This MTA accumulation defines the metabolic shift, signifying the failure of the methionine salvage pathway. Since the cancer cell can no longer recycle purines and methionine from MTA, it becomes uniquely reliant on alternative routes, such as the de novo purine synthesis pathway, to support its rapid growth. The high concentration of MTA also begins to act as an inhibitor, influencing other metabolic enzymes.
Exploiting MTAP Deletion in Treatment
The metabolic vulnerability created by MTAP deletion offers a promising strategy for targeted cancer treatments. This approach utilizes “synthetic lethality,” where the simultaneous loss of two pathways is lethal, but the loss of either one alone is survivable. In MTAP-deleted cancers, MTAP loss is combined with a drug that inhibits a second, parallel pathway.
The accumulated MTA acts as a natural partial inhibitor of Protein Arginine Methyltransferase 5 (PRMT5). Because PRMT5 activity is already dampened by MTA, the cancer cell exists in a vulnerable state. Introducing a drug that inhibits the remaining PRMT5 function selectively kills the MTAP-deleted cell, while healthy cells with normal MTAP activity remain largely unaffected.
New-generation PRMT5 inhibitors, known as MTA-cooperative compounds, are being developed to selectively bind to the PRMT5-MTA complex, maximizing their effect in these specific tumors. This targeted approach offers the potential for precision medicine, guiding therapy based on a patient’s tumor genetics.