{"entity":{"id":"prmt5-mtap","kind":"target","name":"PRMT5 (MTAP-deleted cancers)","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/PRMT5","links":[{"label":"MRTX1719 first-in-human (Cancer Discov 2023)","url":"https://doi.org/10.1158/2159-8290.CD-23-0669"}],"tags":["gap-fill"],"related":[],"cancers":["mesothelioma","glioblastoma","pancreatic","nsclc","urothelial","cholangiocarcinoma"],"sections":[],"technologies":["synthetic-lethality-approaches","cgp","cancer-cell-line-encyclopedias"],"targets":[],"drugs":["navlimetostat","tng462","azd3470","anvumetostat","tng456"],"companies":["amgen","bms","astrazeneca"],"institutions":[],"pathways":[],"terms":["synthetic-lethality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-engstrom-cancer-discov"],"journals":[],"dependsOn":[],"notes":[],"symbol":"PRMT5","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"many-types","specificityNote":"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.)","specificitySources":[{"label":"Human Protein Atlas PRMT5 tissue","url":"https://www.proteinatlas.org/ENSG00000100462-PRMT5/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas MTAP tissue","url":"https://www.proteinatlas.org/ENSG00000099810-MTAP/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000100462 associations","url":"https://platform.opentargets.org/target/ENSG00000100462/associations","note":"cancer associations at or above 0.5 (CC0)"},{"label":"Open Targets ENSG00000099810 associations","url":"https://platform.opentargets.org/target/ENSG00000099810/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:10894","ensembl":"ENSG00000100462","uniprot":"O14744","entrez":"10419","firstDescribed":1998,"firstDescribedBasis":"sequence","firstDescribedNote":"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\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/9556550/","biology":"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.","whereFound":["Mesothelioma (~40% MTAP deletion)","Glioblastoma (~40%)","Pancreatic adenocarcinoma (~20%)","Urothelial carcinoma (~20%)","NSCLC (~15%)","Cholangiocarcinoma, melanoma, sarcoma (subsets)"],"targetClass":"enzyme","prevalence":[{"cancerId":"mesothelioma","pct":"40","measure":"MTAP homozygous deletion"},{"cancerId":"glioblastoma","pct":"40","measure":"MTAP deletion"},{"cancerId":"nsclc","pct":"15","measure":"MTAP deletion"},{"cancerId":"pancreatic","pct":"20","measure":"MTAP deletion"}]},"route":"/targets/prmt5-mtap/","neighbours":{"cancer":[{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"urothelial","kind":"cancer","name":"Bladder & urothelial cancer","route":"/cancers/urothelial/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"mesothelioma","kind":"cancer","name":"Mesothelioma","route":"/cancers/mesothelioma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"cancer-cell-line-encyclopedias","kind":"technology","name":"Cancer cell line encyclopedias and dependency maps","route":"/technologies/cancer-cell-line-encyclopedias/"},{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"drug":[{"id":"anvumetostat","kind":"drug","name":"Anvumetostat","route":"/drugs/anvumetostat/"},{"id":"azd3470","kind":"drug","name":"AZD3470","route":"/drugs/azd3470/"},{"id":"navlimetostat","kind":"drug","name":"Navlimetostat","route":"/drugs/navlimetostat/"},{"id":"tng456","kind":"drug","name":"TNG456","route":"/drugs/tng456/"},{"id":"tng462","kind":"drug","name":"TNG462","route":"/drugs/tng462/"}],"company":[{"id":"amgen","kind":"company","name":"Amgen","route":"/companies/amgen/"},{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}],"term":[{"id":"cdkn2a-homozygous-deletion","kind":"term","name":"CDKN2A/B homozygous deletion","route":"/terms/cdkn2a-homozygous-deletion/"},{"id":"gene-amplification","kind":"term","name":"Gene amplification and copy-number change","route":"/terms/gene-amplification/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"paper":[{"id":"paper-depmap-tsherniak-cell-2017","kind":"paper","name":"Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without","route":"/key-papers/paper-depmap-tsherniak-cell-2017/"},{"id":"paper-engstrom-cancer-discov","kind":"paper","name":"MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer","route":"/key-papers/paper-engstrom-cancer-discov/"}],"pathway":[{"id":"oncogene-activation-two-hit","kind":"pathway","name":"Drivers, passengers & the two-hit model","route":"/pathways/oncogene-activation-two-hit/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"}],"roadmap":[{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","route":"/roadmaps/epigenetics-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}