PDF(Pubmed)
Abstract：
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.
摘要：
胶质母细胞瘤（GBM）是成人最常见的原发性恶性脑肿瘤，很少有有效的治疗方法。EGFR改变，包括截短变体EGFRvIII的表达，是这些肿瘤中最常见的基因组变化之一。已知EGFRvIII优先通过STAT5发出信号，用于GBM中的致癌激活，然而,针对EGFRvIII的靶向治疗迄今取得的临床成功有限.在这项研究中,我们采用了表达EGFRvIII的患者源性异种移植物(PDX)模型来确定GBM中EGFRvIII-STAT5信号轴内治疗易损性的关键点.我们的发现表明，STAT5A和STAT5B旁系同源物的外源表达可增强细胞增殖，并且体内STAT5磷酸化的抑制可与替莫唑胺（TMZ）联合使用可改善总体生存率。STAT5磷酸化独立于JAK1和JAK2信号，相反，需要Src家族激酶（SFK）活性。萨拉卡替尼,一种SFK抑制剂,减弱STAT5的磷酸化并优先使EGFRvIII+GBM细胞相对于野生型EGFR发生凋亡性细胞死亡。组成活性的STAT5A或STAT5B降低了EGFRvIII+细胞中的saracatinib敏感性。在体内,与对照组相比，saracatinib治疗降低了携带EGFRWT肿瘤的小鼠的生存率，然而在EGFRvIII+肿瘤中，用saracatinib联合TMZ治疗优先改善生存率.
