Neoplasia：科学家揭示治疗耐药性脑瘤的新方法

近日，来自威斯康星大学的研究者通过研究解释了为什么难以治愈的脑癌-多形性胶质母细胞瘤（GBM）对于当前的化学疗法有如此高的耐药性。研究者John Kuo博士领导这项脑瘤研究，他们报道了一种成功的联合治疗方法，通过破坏脑癌细胞表皮生长因子（EGFR）受体家族多个成员间的信号传导来治疗此疾病。

已故的美国参议员爱德华-肯尼迪2009年死于GBM这种疾病，在被诊断出患上GBM后，人们的平均寿命仅仅有15个月时间，Kuo的早期研究揭示了GBM癌症干细胞可以逃避当前的疗法，并且促使肿瘤在别处再生。

几年前，研究者建议使用一种以EGFR信号为靶点的工程药物来对抗GBM，因为许多的脑癌患者都携带有EGFR的突变。过度异常的EGFR信号可以刺激癌细胞的生长，尽管西妥昔单抗（一种单克隆抗体药物）在临床上可以成功治疗肺癌、直肠癌等疾病，但是在治疗GBM这种疾病上却并不奏效。

研究者Paul Clark博士表示，西妥昔单抗可以关闭EGFR的活力并且抑制癌细胞的生长。但是癌症干细胞可以通过开启两个EGFR家族受体（ERBB2和ERBB3）来补偿癌细胞，使得癌细胞继续生长。其中一个受体- ERBB2参与到了某些类型的乳腺癌化疗耐药中。幸运的是，另一种被FDA批准的新药阿帕替尼可以抑制ERBB2的活性以及多重EGFR成员的信号途径。

这项研究揭示了癌症干细胞的生长可以被阿帕替尼疗法所抑制，研究者Clark表示，这是一个好消息，因为这些药物疗法主要是瞄准GBM癌细胞生长过快和逃避传统的疗法，而且分子靶向药物对于病人的耐受性较好，副作用也较小。研究者Kuo最后表示，目前临床上使用新药和其它治疗措施治疗脑癌的试验正在进行之中。

相关研究成果已经于近日刊登在了国际肿瘤学权威期刊Neoplasia上。

编译自：Novel Way to Treat Drug-Resistant Brain Tumor Cells

编译者：T.Shen

doi:10.1596/neo.12432
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Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition

Paul Clark, Mari Iida, Daniel M Treisman, Haviryaji Kalluri, Sathyapriya Ezhilan, Michael Zorniak, Deric L Wheeler and John S Kuo

Epidermal growth factor receptor (EGFR) signaling is strongly implicated in glioblastoma (GBM) tumorigenesis. However, molecular agents targeting EGFR have demonstrated minimal efficacy in clinical trials, suggesting the existence of GBM resistance mechanisms. GBM cells with stem-like properties (CSC) are highly efficient at tumor initiation and exhibit therapeutic resistance. In this study, GBM CSC lines showed sphere-forming and tumor initiation capacity after EGF withdrawal from cell culture media, compared with normal neural stem cells (NSCs) that rapidly perished after EGF withdrawal. Compensatory activation of related ERBB family receptors (ERBB2 and ERBB3) was observed in GBM CSCs deprived of EGFR signal (EGF deprivation or cetuximab inhibition), suggesting an intrinsic GBM resistance mechanism for EGFR-targeted therapy. Dual inhibition of EGFR and ERBB2 with lapatinib significantly reduced GBM proliferation in colony formation assays compared to cetuximab-mediated EGFR-specific inhibition. Phosphorylation of downstream ERBB signaling components (AKT, ERK1/2) and GBM CSC proliferation were inhibited by lapatinib. Collectively, these findings show that GBM therapeutic resistance to EGFR inhibitors may be explained by compensatory activation of EGFR-related family members (ERBB2, ERBB3) enabling GBM CSC proliferation, and therefore simultaneous blockade of multiple ERBB family members may be required for more efficacious GBM therapy.