EXTH-63. MTA-COOPERATIVE PRMT5 INHIBITORS ARE EFFICACIOUS IN MTAP-DELETED MALIGNANT PERIPHERAL NERVE SHEATH TUMOR MODELS

Abstract

Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with limited treatment options and poor survival rates, necessitating the development of novel therapeutics. Approximately 25-50% of MPNST harbor loss of the enzyme methylthioadenosine phosphorylase (MTAP) due to a passenger deletion driven by loss of the proximal tumor suppressor gene, CDKN2A. PRMT5 was identified as a selective dependence in MTAP-deleted cells due to the accumulation of the substrate methylthioadenosine (MTA), which is itself an endogenous PRMT5 inhibitor. TNG908 and TNG462 are clinical stage MTA-cooperative PRMT5 inhibitors that demonstrate selectivity for MTAP-deleted cells over MTAP-intact cells of 15X and 45X, respectively. Previous reports show both molecules drive durable tumor regressions in xenograft models of various MTAP-deleted cancer histologies. Here, our objectives are to examine the activity of TNG908 and TNG462 in preclinical MPNST models. METHODS The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. TNG908 and TNG462 were further profiled in two MTAP-deleted MPNST patient-derived xenograft (PDX) models, WU-356 and WU-386. RESULTS Incubation with the MTA-cooperative PRMT5 inhibitors, TNG908 and TNG462, selectively decreased the proliferation of MTAP-deleted MPNST cell lines relative to MTAP-intact MPNST cell lines. TNG908 and TNG462 drove dose-dependent antitumor activity including tumor regressions in the MTAP-deleted MPNST PDX models, WU-356 and WU-386, at well-tolerated doses. CONCLUSIONS The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST.