MTA-Cooperative PRMT5 Inhibitors Are Efficacious in MTAP-Deleted Malignant Peripheral Nerve Sheath Tumor Models.

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with poor prognosis. The enzyme methylthioadenosine phosphorylase (MTAP) is lost in ∼25% to 50% of MPNSTs, which is associated with loss of the tumor suppressor gene CDKN2A. Inhibition of PRMT5 was found to be synthetically lethal in cells with MTAP loss due to accumulation of the substrate methylthioadenosine (MTA), an endogenous PRMT5 inhibitor. TNG908 and TNG462 are clinical-stage MTA-cooperative PRMT5 inhibitors that demonstrate selectivity for MTAP-deleted (null) cells over MTAP-proficient [wild-type (WT)] cells. Both compounds drive durable tumor regressions in various cancer xenograft models with MTAP loss. The proliferative effects of TNG908 and TNG462 on MTAP-null and MTAP WT MPNST cell lines were examined using CellTiter-Glo assays. Target inhibition was verified by western blot. TNG908 and TNG462 were further profiled in two MTAP-null MPNST patient-derived xenograft (PDX) models. We identified homozygous loss of the MTAP gene in ∼54% (7/13) of MPNST PDX lines. Two MTA-cooperative PRMT5 inhibitors, TNG908 and TNG462, reduced cell viability in MTAP-null, but not MTAP WT, HAP1 MTAP-isogenic cell lines. TNG908 and TNG462 selectively decreased cell viability and stimulated cell death in MTAP-null MPNST cells compared with MTAP WT MPNST cells. Finally, TNG908 and TNG462 drove dose-dependent antitumor activity, including tumor regressions in two MTAP-null MPNST PDX models, WU-356 and WU-386, at well-tolerated doses. Clinical-stage MTA-cooperative PRMT5 inhibitors TNG908 and TNG462 are efficacious in MPNST models in vitro and in vivo; therefore, MTA-cooperative PRMT5 inhibitors are promising therapeutic agents for patients with MTAP-deleted MPNSTs. See related commentary by Sheehan et al., p. 4620.