MTAP

  • Methylthioadenosine phosphorylase (MTAP)
  • Gene Location: Chromosome 9 (9p21.3)

Biology

  • The MTAP gene encodes methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway. MTAP catalyzes the conversion of 5′-methylthioadenosine (MTA) into adenine and 5-methylthioribose 1-phosphate, which are subsequently recycled for the biosynthesis of purine nucleotides and methionine.1
  • Recycled adenine supports DNA synthesis and cellular energy metabolism (via ATP), while methionine is an essential amino acid involved in protein synthesis and methylation reactions.1
  • MTAP deletions often occur in conjunction with CDKN2A deletions due to their proximity on chromosome 9p21.3. CDKN2A encodes key tumor suppressors, and its loss contributes to tumorigenesis.2
  • In the absence of MTAP, MTA accumulates intracellularly, leading to partial inhibition of PRMT5 (protein arginine methyltransferase 5), an enzyme involved in RNA splicing, epigenetic regulation, and signal transduction. This creates a potential therapeutic vulnerability, and targeting the PRMT5 axis in MTAP-deleted tumors is an area of active investigation.2

Etiology and Epidemiology

  • MTAP loss occurs in approximately 10% to 15% of non–small cell lung cancer (NSCLC) cases and is frequently associated with co-deletion of tumor suppressor genes, contributing to a more aggressive clinical phenotype and potentially poorer prognosis.3
  • Over 99% of NSCLC tumors with MTAP loss also harbor a CDKN2A deletion, due to their proximity on chromosome 9p21.3.4
  • MTAP deletion is a somatic genomic event, not directly linked to environmental or lifestyle factors. However, patterns in certain molecular subtypes may influence its frequency in specific populations.5
  • MTAP loss has been observed in EGFR-mutated NSCLC, which occurs more commonly in Asian patients and never-smokers. This association may explain observed trends but likely reflects the molecular characteristics of the tumor rather than population-specific predisposition.5

Testing

When to Test:

  • MTAP testing is typically part of a comprehensive genomic panel, often conducted alongside CDKN2A, EGFR, ALK, and KRAS on NGS panels.6
  • While MTAP loss is not currently associated with any FDA-approved targeted therapies, its identification may inform clinical trial eligibility, particularly for studies evaluating protein arginine methyltransferase 5 (PRMT5) or methionine adenosyltransferase 2A (MAT2A) inhibitors that exploit synthetic lethality in MTAP-deleted tumors.6
  • Although MTAP deletion is considered an early genomic event and not typically acquired during disease progression, it may be incidentally identified during rebiopsy or repeat circulating tumor DNA–based next-generation sequencing (NGS) at progression, especially if initial profiling was incomplete.7

Available Testing Methods:

  • NGS is the most widely used method for detecting MTAP deletion. It allows for identification of homozygous deletions, assessment of co-occurring alterations, and efficient genomic profiling from a single assay.8
  • Fluorescence in situ hybridization (FISH) may be used to assess MTAP gene copy number and can provide visual confirmation of gene loss in tumor cells. However, FISH is more limited in scope and is typically used as a confirmatory tool rather than a first-line test.9,10

Guideline Recommendations:

  • MTAP testing is not currently recommended as a standalone biomarker in NSCLC management guidelines (eg, NCCN, ASCO), but it is commonly included as part of broad genomic profiling conducted at diagnosis or progression.
  • Routine testing for MTAP deletion is still emerging, with its primary clinical utility centered around identifying candidates for early-phase clinical trials involving PRMT5 or MAT2A inhibitors that target tumor vulnerabilities created by MTAP loss.7
  • According to NCCN Guidelines v7.2025, comprehensive biomarker testing for advanced NSCLC—including EGFR, ALK, ROS1, BRAF, RET, MET, NTRK, KRAS G12C, NRG1, and HER2 mutations, along with IHC evaluation of HER2, c-MET, and PD-L1 expression—is recommended to guide targeted therapy and immunotherapy selection.11

Targeted Therapy

Approved Agents:

  • No therapies directly target MTAP deletion itself. Instead, MTAP loss is exploited as a biomarker for synthetic lethality, specifically by targeting the tumor’s increased dependence on PRMT5 (protein arginine methyltransferase 5).12

Investigational Agents:

  • GSK33265951313
    • GSK3326595 is a selective, small-molecule inhibitor of PRMT5.
    • Because certain cancers—especially those with MTAP gene deletions—rely heavily on PRMT5 activity for survival, GSK3326595 is being investigated as a targeted therapy that exploits this vulnerability through synthetic lethality. By inhibiting PRMT5, it disrupts critical tumor cell functions, potentially leading to cancer cell death.
    • As of mid-2025, GSK3326595 is still in early-phase clinical trials and has not yet received FDA approval. It is being evaluated in various solid tumors, including NSCLC.
  • Mechanism of Action13-15
    • GSK3326595 is a potent and highly selective small-molecule inhibitor of PRMT5.
    • PRMT5 mediates arginine methylation of histones and other proteins, which regulates gene expression, RNA splicing, and DNA damage repair—processes critical for tumor cell survival.
    • GSK3326595 acts as a competitive inhibitor at the peptide substrate binding site of PRMT5, preventing methylation activity.
    • Importantly, GSK3326595’s high selectivity for PRMT5 reduces off-target effects on other methyltransferases, potentially minimizing adverse effects.
    • The deletion of the MTAP gene causes MTA to continuously build up in the cell, which acts as a natural inhibitor of PRMT5. The reduced efficiency of PRMT5 leads to greater PRMT5 dependency on tumor cells, allowing GSK3326595 to take advantage of this.
    • By binding directly to PRMT only after it is bound to SAM (S-adenosylmethionine), GSK3326595 blocks the substrate site and prevents target proteins from binding to PRMT5, effectively shutting down methylation activity, which stops gene expression and inhibits mRNA splicing.

Investigation Studies:

  • METEOR-1
    • ClinicalTrials.gov: NCT02783300
    • Study design: phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of GSK3326595 in adults with solid tumors, including NSCLC.
    • Key Outcomes: The study identified 400 mg, once daily, as the recommended phase 2 dose, demonstrating a manageable safety profile and encouraging antitumor activity across multiple tumor types; given the frequent MTAP deletions and PRMT5 dependency in NSCLC, these findings support further investigation of GSK3326595 in this patient population.

References

  1. Fan N, Zhang Y, Zou S. Methylthioadenosine phosphorylase deficiency in tumors: a compelling therapeutic target. Front Cell Dev Biol. 2023;11:1173356. doi:10.3389/fcell.2023.1173356.
  2. MTAP deletion promotes cancer-cell dependence on PRMT5. CancerDiscov. 2016; 6 (4):OF11. doi:10.1158/2159-8290.CD-RW2016-030
  3. El-Helali A, Ko EY-L, Wong CHL, et al. 668P The impact of MTAP loss on response to immune checkpoint inhibitors in stage IV NSCLC: a prospective real-world analysis. Ann Oncol. 2024;35:S1654-S1655. doi:10.1016/j.annonc.2024.10.701
  4. Ras signaling: pathways, mutations, and tumor onset. Biology Insights. Published February 7, 2025. Accessed July 14, 2025. https://biologyinsights.com/ras-signaling-pathways-mutations-and-tumor-onset/
  5. Ilonen S, Odintsov I, Shaw A, Sholl L. A complementary role for immunohistochemistry and NGS for detection of MTAP gene deletion in patients with non-small cell lung cancer. Lab Invest. 2025;105(3):103936. doi:1016/j.labinv.2024.103936
  6. Penault-Llorca F, Socinski MA. Emerging molecular testing paradigms in non-small cell lung cancer management-current perspectives and recommendations. Oncologist. 2025;30(3):oyae357. doi:10.1093/oncolo/oyae357.
  7. Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the international association for the study of lung cancer. J Thoracic Oncol. 2021;16(10):1647-1662. doi:10.1016/j.jtho.2021.06.017
  8. Aisner DL, Riely GJ. Non–small cell lung cancer: recommendations for biomarker testing and treatment. JNCCN. 2021;19(5.5):610-613. doi:10.6004/jnccn.2021.5020
  9. Brune MM, Savic Prince S, Vlajnic T, et al. MTAP as an emerging biomarker in thoracic malignancies. Lung Cancer. 2024;197:107963. doi:10.1016/j.lungcan.2024.107963.
  10. Li H, Luo N, Fan C, et al. Assessment of CDKN2A homozygous and heterozygous deletions in gliomas across multiple detection platforms. BMC Cancer. 2025;25(1):1007. doi:10.1186/s12885-025-14266-x
  11. NCCN. Clinical practice guidelines in oncology. NSCLC v.7.2025. Published July 10, 2025. Accessed July 14, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  12. Mauro G. AMG 193 shows preliminary clinical activity in MTAP-deleted solid tumors. OncLive. Published September 16, 2024. Accessed July 14, 2025. https://www.onclive.com/view/amg-193-shows-preliminary-clinical-activity-in-mtap-deleted-solid-tumors/
  13. Feustel K, Falchook GS. Protein arginine methyltransferase 5 (PRMT5) inhibitors in oncology clinical trials: a review. JImmunother Precis Oncol. 2022;5(3):58-67. doi:10.36401/JIPO-22-1
  14. Katya Marjon, Cameron MD, Quang P, et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Reports. 2016;15(3):574-587. doi:10.1016/j.celrep.2016.03.043
  15. Lin H, Wang M, Zhang YW, et al. Discovery of potent and selective covalent protein arginine methyltransferase 5 (PRMT5) inhibitors. ACS Med Chem Lett. 2019;10(7):1033-1038. doi:10.1021/acsmedchemlett.9b00074
  16. Siu LL, Rasco DW, Vinay SP, et al. METEOR-1: a phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumors. Ann Oncol. 2019;30(5):V159. doi:10.1093/annonc/mdz244