# PRMT5 (MTAP-deleted cancers)

Source: https://onco.cc/targets/prmt5-mtap/  
OnCo record `prmt5-mtap` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Target
- Last checked: 2026-09-08
- Tags: gap-fill
- Symbol: PRMT5
- Class: enzyme
- 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.
- Where found: Mesothelioma (~40% MTAP deletion); Glioblastoma (~40%); Pancreatic adenocarcinoma (~20%); Urothelial carcinoma (~20%); NSCLC (~15%); Cholangiocarcinoma, melanoma, sarcoma (subsets)

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/PRMT5
- MRTX1719 first-in-human (Cancer Discov 2023): https://doi.org/10.1158/2159-8290.CD-23-0669

## Connected records

- cancers: [Biliary tract cancer (cholangiocarcinoma)](https://onco.cc/cancers/cholangiocarcinoma/), [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [Mesothelioma](https://onco.cc/cancers/mesothelioma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Cancer cell line encyclopedias and dependency maps](https://onco.cc/technologies/cancer-cell-line-encyclopedias/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- drugs: [Anvumetostat](https://onco.cc/drugs/anvumetostat/), [AZD3470](https://onco.cc/drugs/azd3470/), [Navlimetostat](https://onco.cc/drugs/navlimetostat/), [TNG456](https://onco.cc/drugs/tng456/), [TNG462](https://onco.cc/drugs/tng462/)
- companies: [Amgen](https://onco.cc/companies/amgen/), [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Bristol Myers Squibb](https://onco.cc/companies/bms/)
- terms: [CDKN2A/B homozygous deletion](https://onco.cc/terms/cdkn2a-homozygous-deletion/), [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/), [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- key papers: [Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without](https://onco.cc/key-papers/paper-depmap-tsherniak-cell-2017/), [MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer](https://onco.cc/key-papers/paper-engstrom-cancer-discov/)
- pathways: [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/)
- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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JSON: https://onco.cc/api/v1/entities/prmt5-mtap.json