DDDR-64. MTA-Cooperative PRMT5 Inhibitors Demonstrate Efficacy in MTAP-Deleted MPNST Models and Enhance Chemotherapy Response

Abstract Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options and poor prognosis, underscoring the urgent need for novel targeted therapies. Approximately 25-50% of MPNSTs harbor homozygous deletion of methylthioadenosine phosphorylase (MTAP) due to co-deletion with the adjacent tumor suppressor CDKN2A. MTAP loss results in accumulation of methylthioadenosine (MTA), an endogenous inhibitor of PRMT5 (protein arginine methyltransferase 5), creating a selective dependency on PRMT5 in MTAP-deleted tumors. TNG908 and TNG462 are clinical-stage, MTA-cooperative PRMT5 inhibitors that demonstrate selectivity for MTAP-deleted versus MTAP-intact cells. In this study, we evaluated the preclinical efficacy of TNG908 and TNG462 in MPNST. METHODS The effects of TNG908 and TNG462 on proliferation and apoptosis were examined using CellTiter-Glo and IncuCyte assays in MTAP-null (JH-2-079, WU-356, and JH-2-002) and MTAP wild-type (WT) (JH-2-009 and JH-2-031) MPNST cell lines. Target inhibition was verified by WES western system. TNG908 and TNG462 were further profiled in two MTAP-null MPNST patient-derived xenograft (PDX) mouse models. RESULTS Homozygous deletion of the MTAP gene was detected in approximately 54% (7/13) of MPNST PDX models. Two MTA-cooperative PRMT5 inhibitors, TNG908 and TNG462, selectively decreased cell viability and stimulated cell death in MTAP-null compared to MTAP WT MPNST cell lines. Mechanistic analyses revealed induction of apoptosis as evidenced by increased cleavage of caspase-3 and PARP-1. Furthermore, the combination of a PRMT5 inhibitor with doxorubicin or trabectedin had additive antiproliferative effects. In vivo, TNG908 and TNG462 demonstrated dose-dependent antitumor activity in MTAP-null MPNST PDX models WU-356 and WU-386, inducing tumor regressions at well-tolerated doses. CONCLUSION TNG908 and TNG462 selectively inhibited MTAP-deleted MPNST cell growth in vitro and induced tumor regressions in vivo through PRMT5 inhibition and apoptosis induction. These findings support the therapeutic potential of MTA-cooperative PRMT5 inhibitors as a targeted treatment strategy for patients with MTAP-deleted MPNST.