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An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials.
Homozygous deletion of MTAP (co-deleted with CDKN2A on 9p21) causes accumulation of MTA, which partially inhibits PRMT5, leaving MTAP-null cells hypersensitive to further PRMT5 inhibition. MTA-cooperative PRMT5 inhibitors (AMG 193, MRTX1719/BMS-986504, TNG908, TNG462, AZD3470) exploit this synthetic lethality with a wide therapeutic window compared with first-generation PRMT5 inhibitors (which caused thrombocytopenia). Responses have been reported in MTAP-deleted NSCLC, mesothelioma, pancreatic and biliary cancers; combination with KRAS G12C inhibitors is being tested and phase 3 trials began in 2025-26. MTAP deletion occurs in ~40% of mesothelioma and glioblastoma, ~20% of pancreatic cancer and bladder cancer, ~15% of NSCLC.
In plain words · An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials.
An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials.
Type II protein arginine methyltransferase forming symmetric dimethylarginine on histones (H4R3, H3R8) and splicing factors (SmD3); essential for spliceosome function; MTA is a competitive SAM-site inhibitor accumulating when MTAP is lost.
5 products aim at PRMT5 (MTAP-deleted cancers): small molecules. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Broadly expressed or essential: HPA lists PRMT5 among essential proteins and finds the RNA at low tissue specificity; the 5 medicines aimed at it (Navlimetostat, TNG462, AZD3470 and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA PRMT5: RNA low tissue specificity; high antibody staining in 9 normal tissues; highest cancer staining breast cancer (7 of 11 high). HPA MTAP: RNA low tissue specificity; high antibody staining in 8 normal tissues; highest cancer staining ovarian cancer (3 of 12 high). Distribution: 6 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Mesothelioma, Brain and spinal cord tumours (all types), Lung cancer (all types), Pancreatic ductal adenocarcinoma, Bladder & urothelial cancer, Biliary tract cancer (all types)); Open Targets associates it with 3 specific cancer types at or above 0.5 (diaphyseal medullary stenosis-bone malignancy syndrome, cutaneous melanoma, melanoma). (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas PRMT5 tissue; Human Protein Atlas MTAP tissue; Open Targets ENSG00000100462 associations; Open Targets ENSG00000099810 associations
First described 1998. Earliest sequence paper UniProt cites for the protein: Krapivinsky et al, J. Biol. Chem, 1998, "pICln binds to a mammalian homolog of a yeast protein involved in regulation of cell morphology". Source.
Type II protein arginine methyltransferase forming symmetric dimethylarginine on histones (H4R3, H3R8) and splicing factors (SmD3); essential for spliceosome function; MTA is a competitive SAM-site inhibitor accumulating when MTAP is lost.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adrenal gland, Appendix, Caudate, Cerebellum, Cerebral cortex, Endometrium, Esophagus, Gallbladder.
Medium only: endometrial cancer, head and neck cancer, lung cancer, renal cancer.
HPA PRMT5 tissue · HPA PRMT5 pathology · HPA protein class: Essential proteins
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adrenal gland, Caudate, Colon, Endometrium, Esophagus, Fallopian tube, Hippocampus, Lung.
Medium only: breast cancer, colorectal cancer, endometrial cancer, glioma.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Mesothelioma | 40% | MTAP homozygous deletion | ||
| Glioma & glioblastoma | 40% | MTAP deletion | ||
| Pancreatic ductal adenocarcinoma | 20% | MTAP deletion | ||
| Non-small-cell lung cancer | 15% | MTAP deletion |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Anvumetostat is an experimental small-molecule drug from Amgen in phase 2 trials for non-small-cell lung cancer, aimed at PRMT5 (MTAP-deleted cancers).
AZD3470 is an experimental small-molecule drug from AstraZeneca in phase 2 trials for hodgkin lymphoma and peripheral T-cell lymphomas, aimed at PRMT5 (MTAP-deleted cancers).
Navlimetostat is an experimental small-molecule drug from Bristol-Myers Squibb in phase 3 trials for non-small-cell lung cancer and pancreatic ductal adenocarcinoma, aimed at PRMT5 (MTAP-deleted cancers).
TNG456 is an experimental small-molecule drug from Tango Therapeutics in phase 2 trials for non-small-cell lung cancer and glioma & glioblastoma, aimed at PRMT5 (MTAP-deleted cancers).
TNG462 is an experimental small-molecule drug from Tango Therapeutics in phase 2 trials for pancreatic ductal adenocarcinoma and non-small-cell lung cancer, aimed at PRMT5 (MTAP-deleted cancers).
One target page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
DepMap is the lookup table drug hunters use to ask: which cancers would die if we blocked this gene, and how would we recognise them? It generated targets such as WRN and PRMT5-MTAP now in clinical trials, and it is public.
Query for this target: (TITLE:"PRMT5" OR ABSTRACT:"PRMT5" OR TITLE:"MTAP-deleted cancers" OR ABSTRACT:"MTAP-deleted cancers") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about PRMT5 (MTAP-deleted cancers), not a curated reading list.
Shares Cancer cell line encyclopedias and dependency maps, Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without, Synthetic lethality, Synthetic lethality: paired dependencies.
Shares Anvumetostat, Amgen, Non-small-cell lung cancer.
Shares TNG456, TNG462, Synthetic lethality approaches, Glioma & glioblastoma.
Shares Navlimetostat, Bristol Myers Squibb, Non-small-cell lung cancer.
Shares Navlimetostat, Bristol Myers Squibb, Pancreatic ductal adenocarcinoma.
Shares TNG456, Glioma & glioblastoma, Non-small-cell lung cancer.
Shares Anvumetostat, Amgen.
Shares Synthetic lethality, Synthetic lethality approaches, Amgen.