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About half of mesotheliomas have lost a gene called MTAP. That loss creates a weakness that new PRMT5 inhibitors are designed to exploit.
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.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.
Shares Synthetic lethality approaches, CRISPR functional genomics.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.
Shares Synthetic lethality approaches, CRISPR functional genomics.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.