# PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma

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

## TL;DR

About half of mesotheliomas have lost a gene called MTAP. That loss creates a weakness that new PRMT5 inhibitors are designed to exploit.

## Summary

Roughly half of pleural mesotheliomas carry a co-deletion of CDKN2A and MTAP, and this idea proposes exploiting the weakness that MTAP loss creates. Loss of MTAP raises intracellular MTA, which partially inhibits PRMT5, so MTA-cooperative PRMT5 inhibitors such as AMG 193, MRTX1719 and BMS-986504, and MAT2A inhibitors, gain a therapeutic window that first-generation PRMT5 inhibitors lacked. The rationale is a strong genetic dependency in DepMap, an easy immunohistochemistry test for MTAP loss, and early responses in MTAP-deleted tumours including mesothelioma. At an early clinical stage, the test would be expansion cohorts then a randomised second-line trial, and it connects to the ideas on attacking the backup copy of a lost gene and grouping trials by broken mechanism.

## Fields

- Kind: Idea
- Last checked: 2026-09-07
- Hypothesis: MTA-cooperative PRMT5 inhibitors will produce durable responses in MTAP-deleted mesothelioma after immunotherapy, with a therapeutic window absent for first-generation PRMT5 inhibitors.
- Rationale: Strong genetic dependency in DepMap; MTAP deletion is easily tested by IHC; mesothelioma has among the highest MTAP-loss frequencies of any cancer.
- Proposed test: MTAP-deleted mesothelioma expansion cohorts in ongoing phase 1/2 trials, then a randomised second-line trial versus chemotherapy.
- Maturity: early-clinical

## Sources

- Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without (Cell 2017): https://doi.org/10.1016/j.cell.2017.06.010

## Connected records

- cancers: [Mesothelioma](https://onco.cc/cancers/mesothelioma/)
- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- terms: [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- ideas: [Attack the backup copy when a tumour has lost the original gene](https://onco.cc/ideas/idea-bio1-paralog-synthetic-lethality/), [Group trials by broken mechanism, not by organ or single mutation](https://onco.cc/ideas/idea-bio2-mechanism-defined-baskets/)

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