Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, MA, USA.
Oncogene. 2021 Apr;40(15):2682-2696. doi: 10.1038/s41388-021-01721-9. Epub 2021 Mar 11.
Focal amplification of epidermal growth factor receptor (EGFR) and its ligand-independent, constitutively active EGFRvIII mutant form are prominent oncogenic drivers in glioblastoma (GBM). The EGFRvIII gene rearrangement is considered to be an initiating event in the etiology of GBM, however, the mechanistic details of how EGFRvIII drives cellular transformation and tumor maintenance remain unclear. Here, we report that EGFRvIII demonstrates a reliance on PDGFRA co-stimulatory signaling during the tumorigenic process in a genetically engineered autochthonous GBM model. This dependency exposes liabilities that were leveraged using kinase inhibitors treatments in EGFRvIII-expressing GBM patient-derived xenografts (PDXs), where simultaneous pharmacological inhibition of EGFRvIII and PDGFRA kinase activities is necessary for anti-tumor efficacy. Our work establishes that EGFRvIII-positive tumors have unexplored vulnerabilities to targeted agents concomitant to the EGFR kinase inhibitor repertoire.
表皮生长因子受体 (EGFR) 的局灶扩增及其配体非依赖性、组成性激活的 EGFRvIII 突变形式是胶质母细胞瘤 (GBM) 中突出的致癌驱动因素。EGFRvIII 基因重排被认为是 GBM 病因学中的一个起始事件，然而，EGFRvIII 如何驱动细胞转化和肿瘤维持的机制细节仍不清楚。在这里，我们报告在遗传工程源性 GBM 模型中，EGFRvIII 在致瘤过程中依赖 PDGFRA 共刺激信号。这种依赖性暴露了一些缺陷，这些缺陷可通过激酶抑制剂治疗来利用，在表达 EGFRvIII 的 GBM 患者来源异种移植物 (PDX) 中，同时抑制 EGFRvIII 和 PDGFRA 激酶活性对于抗肿瘤疗效是必需的。我们的工作表明，EGFRvIII 阳性肿瘤对靶向药物具有尚未被探索的脆弱性，这些药物与 EGFR 激酶抑制剂联合使用。
