Methylthioadenosine phosphorylase, commonly known as MTAP, is an enzyme involved in cellular metabolism. While MTAP’s proper function is important for healthy cell processes, its absence or loss of activity, known as “MTAP loss,” becomes a significant factor in certain biological contexts, particularly in cancer. This loss can alter cell function and response, creating unique vulnerabilities.
What is MTAP and Its Role
MTAP is an enzyme involved in the methionine salvage pathway, which recycles sulfur-containing metabolites back into methionine. This pathway maintains the cellular balance of essential molecules like methionine and purine nucleotides. Methionine is an amino acid necessary for various cellular processes, including protein synthesis and providing methyl groups for biological methylation reactions.
MTAP catalyzes the reversible phosphorolysis of 5′-deoxy-5′-methylthioadenosine (MTA) into adenine and 5-methylthioribose-1-phosphate. MTA is a byproduct of polyamine biosynthesis, important for cell growth. These products are then recycled to produce methionine and purine nucleotides. This recycling helps ensure the efficient use of methionine and the maintenance of purine levels.
Why MTAP Loss Occurs and Its Cellular Impact
MTAP loss occurs due to a genetic deletion. The MTAP gene is located on chromosome 9p21.3, near the CDKN2A tumor suppressor gene. Due to their close proximity, these two genes are often co-deleted. This co-deletion of MTAP with CDKN2A is observed in approximately 10-15% of all human cancers.
MTAP deficiency leads to the accumulation of methylthioadenosine (MTA). Without functional MTAP, MTA cannot be converted into adenine and 5-methylthioribose-1-phosphate, leading to its buildup within the cell. This accumulation inhibits the activity of other enzymes, particularly Protein Arginine Methyltransferase 5 (PRMT5). The altered metabolic state due to MTA accumulation creates specific vulnerabilities, making cells with MTAP loss more sensitive to disruptions in methionine availability and purine synthesis.
MTAP Loss and Its Connection to Cancer
MTAP loss is observed across various human cancers, including melanoma, lung cancer, pancreatic cancer, and glioblastoma. MTAP deficiency contributes to tumor development and progression by impacting several cellular pathways. For instance, MTA accumulation due to MTAP loss can partially inhibit PRMT5 activity, which regulates processes like the cell cycle, DNA repair, and gene expression.
A key concept in MTAP loss and cancer is “synthetic lethality.” This describes a situation where the simultaneous loss of two genes or pathways leads to cell death, while the loss of either one alone does not. In MTAP-deficient cells, MTA accumulation reduces PRMT5 activity, making these cells vulnerable to further PRMT5 inhibition. This means therapies targeting PRMT5 can selectively harm MTAP-deficient cancer cells while sparing healthy cells that retain MTAP function.
Therapeutic Approaches for MTAP-Deficient Cancers
Understanding MTAP loss and its synthetic lethal relationship with PRMT5 has paved the way for targeted therapeutic strategies. PRMT5 inhibitors are promising drugs designed to exploit this vulnerability. These inhibitors aim to further suppress PRMT5 activity in MTAP-deficient cancer cells, leading to their death. Clinical trials are currently evaluating the safety and efficacy of PRMT5 inhibitors, such as MRTX1719, in patients with advanced or metastatic MTAP-deleted solid tumors.
Beyond PRMT5 inhibition, other strategies are being explored to exploit the unique metabolic vulnerabilities of MTAP-deficient cells. For example, research suggests that MTAP-deficient cancer cells may exhibit increased glycolysis and de novo purine synthesis to compensate for their metabolic defects. This opens avenues for combination therapies, such as combining PRMT5 inhibitors with agents that target methionine adenosyltransferase II alpha (MAT2A), an enzyme that produces S-adenosylmethionine (SAM), a substrate for PRMT5. Such combinations aim to create a synergistic anti-tumor effect.