抑制Polo样激酶1对EGFRvIII高表达脑胶质瘤的合成致死作用及其机制

Synthetic lethality has provided a brand new strategy to screen the anti-tumor drugs. For example, PARP1 and BRCA1/2 have a relationship of synthetic lethality, which has been successfully used in anti-tumor therapy. However, the synthetic lethal partner of consistantly active mutant EGFR type III variant (EGFRvIII), which is overexpressing in approximately 25% glioblastoma tumors, hasn't been reported yet. EGFRvIII overexpressing is associated with malignancy progression and drug resistance. We carried out a siRNA screen to identify synthetic lethal partners of the oncogenic EGFRvIII in glioblastoma cells and identified polo-like kinase 1 (PLK1). In vitro and in vivo experiments have confirmed that PLK1 inhibition by PLK1 siRNA or PLK1 inhibitor, BI2536, significantly inhibit the proliferation and tumor growth of EGFRvIII overexpressing GBM cells and induced EGFR inhibitor resistant clones, while minor effects were seen in the normal astrocytes. The effect of PLK1 inhibition on the endogenous EGFRvIII overexpressing glioblastoma would be determined. Mechanistically, the interaction of PLK1 with DNA damage checkpoints and DNA damage repair pathways needs to be evaluated furtherly, which provides the evidence of PLK1 as a promising synthetic lethal target for the potential treatment of glioblastoma harboring EGFRvIII.

合成致死（synthetic lethality）为抗肿瘤靶向药物筛选提供了崭新思路，如抑制PARP1与BRCA1/2缺失构成合成致死关系已成功运用于抗肿瘤临床治疗，而在脑胶质瘤（GBM）中常见的EGFRvIII突变体高表达对应的合成致死靶点尚未见报道，EGFRvIII高表达是GBM恶化和耐受EGFR抑制剂的主要原因。我们通过siRNA文库高通量筛选和体内外实验验证发现，抑制polo样激酶1（PLK1） 对外源性EGFRvIII稳定高表达的GBM细胞及其耐药株均有显著抑制作用，对正常星形细胞影响很小。本项目拟在内源性EGFRvIII高表达GBM中进一步阐明抑制PLK1的合成致死作用，并探讨其分子机制，PLK1作为EGFRvIII合成致死潜在靶点，有望为EGFRvIII高表达脑胶质瘤临床靶向药物治疗提供新方案。

合成致死（synthetic lethality）为抗肿瘤靶向药物筛选提供了崭新思路，如抑制PARP1与BRCA1/2缺失构成合成致死关系已成功运用于抗肿瘤临床治疗，而在脑胶质瘤（GBM）中常见的EGFRvIII突变体高表达对应的合成致死靶点尚未见报道，EGFRvIII高表达是GBM恶化和耐受EGFR-TKI 靶向药物的主要原因。我们通过siRNA文库高通量筛选和体内外实验验证发现，抑制polo样激酶1（PLK1）对外源性EGFRvIII稳定高表达的GBM细胞及其耐药株均有显著抑制作用，对正常星形细胞影响很小。PLK1 抑制剂 BI2536 能显著提高 EGFR 活化突变 (EGFRvIII) 阳性脑胶质瘤细胞对一线化疗药物替莫唑胺 (TMZ) 和 EGFR-TKI 靶向药物 Gefitinib 和 Erlotinib 的敏感性。深入探讨其机制发现EGFRvIII 高表达脑胶质瘤细胞依赖于 PLK1 参与调控同源重组损伤修复途径关键酶 Rad51 活性，BI2536 处理后能够明显抑制 Rad51 磷酸化水平，PLK1作为EGFRvIII合成致死潜在靶点，有望为EGFRvIII高表达脑胶质瘤临床靶向药物治疗提供新方案。