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MTA-Cooperative PRMT5 Inhibitors Are Efficacious in MTAP-Deleted Malignant Peripheral Nerve Sheath Tumor Models
Xiaochun Zhang1, Dana C Borcherding1, Minjie Zhang2
1Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Purpose:
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.
Experimental Design:
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.
Results:
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.
Conclusions:
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.
Insights
New PRMT5 inhibitors, TNG908 and TNG462, show promise for treating malignant peripheral nerve sheath tumors (MPNST) that lack the MTAP enzyme. These drugs effectively reduced tumor growth in preclinical models, offering a potential new therapy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with a poor prognosis.
- Approximately 25-50% of MPNST exhibit a loss of the methylthioadenosine phosphorylase (MTAP) enzyme, often linked to CDKN2A tumor suppressor gene deletion.
- Loss of MTAP creates synthetic lethality in cancer cells through the accumulation of methylthioadenosine (MTA), an endogenous inhibitor of PRMT5.
Purpose of the Study:
- To evaluate the efficacy of MTA-cooperative PRMT5 inhibitors, TNG908 and TNG462, in preclinical models of MPNST.
- To determine the selectivity of TNG908 and TNG462 for MTAP-deleted (null) MPNST cells compared to MTAP-proficient (WT) cells.
- To assess the in vitro and in vivo anti-tumor activity of TNG908 and TNG462 in MPNST models.
Main Methods:
- Assessed the proliferative effects of TNG908 and TNG462 on MTAP-null and MTAP WT MPNST cell lines using CellTiter-Glo assays.
- Verified target inhibition of PRMT5 by western blot analysis.
- Profiled TNG908 and TNG462 in two MTAP-null MPNST patient-derived xenograft (PDX) models.
Main Results:
- Homozygous loss of the MTAP gene was identified in approximately 54% of tested MPNST PDX lines.
- TNG908 and TNG462 significantly reduced cell viability in MTAP-null MPNST cell lines but not in MTAP WT cell lines.
- Both TNG908 and TNG462 demonstrated dose-dependent anti-tumor activity, including complete tumor regressions, in two MTAP-null MPNST PDX models at well-tolerated doses.
Conclusions:
- Clinical-stage MTA-cooperative PRMT5 inhibitors TNG908 and TNG462 exhibit significant efficacy in both in vitro and in vivo MPNST models.
- These findings suggest that MTA-cooperative PRMT5 inhibitors represent a promising therapeutic strategy for patients with MTAP-deleted MPNST.
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