{"entity":{"id":"idea-mtap-prmt5-mesothelioma","kind":"idea","name":"PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma","aka":[],"tldr":"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.","asOf":"2026-09-07","links":[{"label":"Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without (Cell 2017)","url":"https://doi.org/10.1016/j.cell.2017.06.010"}],"tags":[],"related":[],"cancers":["mesothelioma"],"sections":[],"technologies":["synthetic-lethality-approaches","crispr-screens"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["synthetic-lethality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","test":"MTAP-deleted mesothelioma expansion cohorts in ongoing phase 1/2 trials, then a randomised second-line trial versus chemotherapy.","maturity":"early-clinical"},"route":"/ideas/idea-mtap-prmt5-mesothelioma/","neighbours":{"cancer":[{"id":"mesothelioma","kind":"cancer","name":"Mesothelioma","route":"/cancers/mesothelioma/"}],"technology":[{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"term":[{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"idea":[{"id":"idea-bio1-paralog-synthetic-lethality","kind":"idea","name":"Attack the backup copy when a tumour has lost the original gene","route":"/ideas/idea-bio1-paralog-synthetic-lethality/"},{"id":"idea-bio2-mechanism-defined-baskets","kind":"idea","name":"Group trials by broken mechanism, not by organ or single mutation","route":"/ideas/idea-bio2-mechanism-defined-baskets/"}]}}