Zhang Xiaochun, Borcherding Dana C, Zhang Minjie, Lyu Yang, Wang Guangfeng, He Kevin, Oztosun Gorkem, Sachdeva Ishita, Yang Liuzhan, Yang Kuangying, Yuen Alex, DiBenedetto Heather, Tsai Alice, Huang Alan, Maxwell John P, Cottrell Kevin M, Briggs Kimberly J, Hirbe Angela C
Washington University in St. Louis, Saint Louis, MO, United States.
Washington University School of Medicine, St. Louis, MO, United States.
Clin Cancer Res. 2025 Jun 24. doi: 10.1158/1078-0432.CCR-24-3610.
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with poor prognosis. The enzyme methylthioadenosine phosphorylase (MTAP) is lost in ~25-50% of MPNST, 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 (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 the cell viability of MTAP-null JH-2-079 MPNST cells compared to MTAP WT JH-2-009 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 MPNST.
恶性外周神经鞘瘤（MPNST）是具有高度侵袭性且预后较差的肉瘤。约25% - 50%的MPNST中会出现甲硫腺苷磷酸化酶（MTAP）缺失，这与肿瘤抑制基因CDKN2A的缺失相关。由于底物甲硫腺苷（MTA，一种内源性PRMT5抑制剂）的积累，发现对PRMT5的抑制在MTAP缺失的细胞中具有合成致死性。TNG908和TNG462是临床阶段的MTA协同PRMT5抑制剂，对MTAP缺失（无效）细胞比MTAP正常（野生型）细胞具有选择性。这两种化合物在多种具有MTAP缺失的癌症异种移植模型中均能促使肿瘤持久消退。
使用CellTiter - Glo检测法检测TNG908和TNG462对MTAP缺失和MTAP野生型MPNST细胞系的增殖作用。通过蛋白质免疫印迹法验证靶点抑制情况。TNG908和TNG462在两种源自MPNST患者的MTAP缺失的异种移植（PDX）模型中进一步进行分析。
我们在约54%（7/13）的MPNST PDX系中鉴定出MTAP基因的纯合缺失。两种MTA协同PRMT5抑制剂TNG908和TNG462降低了MTAP缺失的HAP1 MTAP同基因细胞系的细胞活力，但对MTAP野生型细胞系无此作用。与MTAP野生型JH - 2 - 009 MPNST细胞相比，TNG908和TNG462选择性降低了MTAP缺失的JH - 2 - 079 MPNST细胞的细胞活力。最后，TNG908和TNG462在耐受性良好的剂量下呈现出剂量依赖性的抗肿瘤活性，包括在两种MTAP缺失的MPNST PDX模型WU - 356和WU - 386中使肿瘤消退。
临床阶段的MTA协同PRMT5抑制剂TNG908和TNG462在体外和体内的MPNST模型中均有效；因此，MTA协同PRMT5抑制剂对于MTAP缺失的MPNST患者是有前景的治疗药物。
