EGFRvIII expression triggers a metabolic dependency and therapeutic vulnerability sensitive to autophagy inhibition

Expression of EGFRvIII is frequently observed in glioblastoma and is associated with increased cellular proliferation, enhanced tolerance to metabolic stresses, accelerated tumor growth, therapy resistance and poor prognosis. We observed that expression of EGFRvIII elevates the activation of macroautophagy/autophagy during starvation and hypoxia and explored the underlying mechanism and consequence. Autophagy was inhibited (genetically or pharmacologically) and its consequence for tolerance to metabolic stress and its therapeutic potential in (EGFRvIII⁺) glioblastoma was assessed in cellular systems, (patient derived) tumor xenopgrafts and glioblastoma patients. Autophagy inhibition abrogated the enhanced proliferation and survival advantage of EGFRvIII⁺ cells during stress conditions, decreased tumor hypoxia and delayed tumor growth in EGFRvIII⁺ tumors. These effects can be attributed to the supporting role of autophagy in meeting the high metabolic demand of EGFRvIII⁺ cells. As hypoxic tumor cells greatly contribute to therapy resistance, autophagy inhibition revokes the radioresistant phenotype of EGFRvIII⁺ tumors in (patient derived) xenograft tumors. In line with these findings, retrospective analysis of glioblastoma patients indicated that chloroquine treatment improves survival of all glioblastoma patients, but patients with EGFRvIII⁺ glioblastoma benefited most. Our findings disclose the unique autophagy dependency of EGFRvIII⁺ glioblastoma as a therapeutic opportunity. Chloroquine treatment may therefore be considered as an additional treatment strategy for glioblastoma patients and can reverse the worse prognosis of patients with EGFRvIII⁺ glioblastoma.

表皮生长因子受体变异体III（EGFRvIII）的表达在胶质母细胞瘤（glioblastoma）中较为常见，且与细胞增殖增强、代谢应激耐受提升、肿瘤生长加速、治疗抵抗及不良预后密切相关。本研究观察到，在饥饿与缺氧状态下，EGFRvIII的表达可升高巨自噬/自噬（macroautophagy/autophagy）的激活水平，并对其潜在机制与生物学效应进行了探索。我们通过基因或药理学手段抑制自噬，并在细胞模型、患者来源（patient derived）肿瘤异种移植瘤以及胶质母细胞瘤患者中，评估了自噬抑制对代谢应激耐受的影响，及其在EGFRvIII⁺胶质母细胞瘤中的治疗潜力。实验结果显示，自噬抑制可消除EGFRvIII⁺细胞在应激状态下的增殖与生存优势，降低EGFRvIII⁺肿瘤的缺氧程度，并延缓其生长速度。上述效应可归因于自噬在满足EGFRvIII⁺细胞高代谢需求过程中发挥的支持作用。由于缺氧肿瘤细胞是治疗抵抗的重要诱因，自噬抑制可逆转患者来源异种移植瘤中EGFRvIII⁺肿瘤的放射抵抗表型。与上述实验发现相符的是，对胶质母细胞瘤患者的回顾性分析表明，氯喹治疗可改善所有胶质母细胞瘤患者的生存结局，但EGFRvIII⁺胶质母细胞瘤患者获益最为显著。本研究揭示了EGFRvIII⁺胶质母细胞瘤独特的自噬依赖性，为该类肿瘤提供了全新的治疗机遇。因此，氯喹治疗可作为胶质母细胞瘤患者的辅助治疗策略，且可逆转EGFRvIII⁺胶质母细胞瘤患者的不良预后。