Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma
Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma
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DOI：
10.1093/neuonc/noz127
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发表时间：
2019-12-01
期刊：
影响因子：
15.9
通讯作者：
Habib, Amyn A.
中科院分区：
文献类型：
--
作者：
Guo, Gao;Gong, Ke;Habib, Amyn A.
背景。胶质母细胞瘤 (GBM) 是最常见的原发性恶性成人脑肿瘤。替莫唑胺 (TMZ) 是标准治疗方法，对于缺乏 DNA 修复蛋白 O-6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 的 GBM 最为有效。此外，即使最初有反应的肿瘤也会对 TMZ 产生继发性耐药，从而变得无法治疗。由于异常的表皮生长因子受体 (EGFR) 信号传导在 GBM 中广泛存在，因此在多项临床试验中尝试了 EGFR 抑制，但没有成功。我们最近报道，抑制 EGFR 会导致肿瘤坏死因子 (TNF) 分泌增加并激活 GBM 中的生存途径。在这里，我们比较了 TMZ 与 EGFR 加 TNF 抑制在 GBM 原位小鼠模型中的疗效。方法。我们使用原位模型来检查 TMZ 相对于 EGFR 加 TNF 抑制在多个 GBM 子集中的功效，包括 MGMT 甲基化和未甲基化的原发性 GBM、复发性 GBM 以及实验上对 TMZ 耐药的 GBM。结果。两种治疗方法在 MGMT 甲基化 GBM 中的疗效相似。然而，在 MGMT 非甲基化 GBM 中，EGFR 加 TNF 抑制的组合更有效。我们证明这两种治疗方法针对不同且不重叠的途径。因此，重要的是，EGFR加TNF抑制对于TMZ耐药的复发性GBM和实验上对TMZ耐药的GBM仍然有效。结论。 EGFR 抑制结合减弱 TNF 驱动的适应性反应可能是 MGMT 非甲基化和复发性 EGFR 表达 GBM 的可行治疗方法。
Background. Glioblastoma (GBM) is the most common primary malignant adult brain tumor.Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM.Methods. We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ.Results. The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plusTNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ.Conclusion. EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.