ideasIdea
PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma
About half of mesotheliomas have lost a gene called MTAP. That loss creates a weakness that new PRMT5 inhibitors are designed to exploit.
CDKN2A/MTAP co-deletion occurs in ~40-50% of pleural mesotheliomas. MTAP loss raises MTA, which partially inhibits PRMT5; MTA-cooperative PRMT5 inhibitors (AMG 193, MRTX1719, BMS-986504) and MAT2A inhibitors show early responses in MTAP-deleted tumours including mesothelioma.
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.
What would test it
MTAP-deleted mesothelioma expansion cohorts in ongoing phase 1/2 trials, then a randomised second-line trial versus chemotherapy.
Maturity
early clinical