Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition.
Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition.
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通过同时抑制 EGFR 和 PLK1 正交靶向表达 EGFRvIII 的胶质母细胞瘤。
DOI：
10.18632/oncotarget.3996
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发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Chen CC
中科院分区：
文献类型：
--
作者：
Shen Y;Li J;Nitta M;Futalan D;Steed T;Treiber JM;Taich Z;Stevens D;Wykosky J;Chen HZ;Carter BS;Becher OJ;Kennedy R;Esashi F;Sarkaria JN;Furnari FB;Cavenee WK;Desai A;Chen CC
我们确定了PLK 1沉默和致癌表皮生长因子受体EGFRvIII表达之间的合成致死性。PLK 1促进同源重组（HR），减轻EGFRvIII诱导的由DNA损伤积累引起的致癌应激。因此，PLK 1抑制增强了DNA损伤剂替莫唑胺（TMZ）的细胞毒性作用。相对于Ink 4a/Arf（−/−）PDGF-β模型，该效应在Ink 4a/Arf（−/−）EGFRvIII胶质母细胞瘤模型中显著更明显。在对EGFR抑制剂获得独立耐药机制的Ink 4a/Arf（−/−）EGFRvIII胶质母细胞瘤克隆中一致观察到BI 2536的杀肿瘤和TMZ致敏作用，表明这些耐药克隆保留了需要PLK 1补偿的致癌应激。尽管BI 2536显著增强了Ink 4a/Arf（−/−）EGFRvIII模型中EGFR抑制剂的抗肿瘤作用，但直到加入TMZ后才实现持久的缓解。我们的研究结果表明，针对胶质母细胞瘤的最佳治疗效果需要针对与靶癌症基因组相关的分子生理学定制的“多正交”组合。
We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(−/−) EGFRvIII glioblastoma model relative to an Ink4a/Arf(−/−) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(−/−) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/Arf(−/−) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a “multi-orthogonal” combination tailored to the molecular physiology associated with the target cancer genome.
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通讯作者：
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