近日,，來自威斯康星大學的研究者通過研究解釋了為什么難以治愈的腦癌-多形性膠質(zhì)母細胞瘤（GBM）對于當前的化學療法有如此高的耐藥性。研究者John Kuo博士領(lǐng)導這項腦瘤研究，他們報道了一種成功的聯(lián)合治療方法,，通過破壞腦癌細胞表皮生長因子（EGFR）受體家族多個成員間的信號傳導來治療此疾病,。
已故的美國參議員愛德華-肯尼迪2009年死于GBM這種疾病，在被診斷出患上GBM后,，人們的平均壽命僅僅有15個月時間,，Kuo的早期研究揭示了GBM癌癥干細胞可以逃避當前的療法，并且促使腫瘤在別處再生,。
幾年前,，研究者建議使用一種以EGFR信號為靶點的工程藥物來對抗GBM，因為許多的腦癌患者都攜帶有EGFR的突變,。過度異常的EGFR信號可以刺激癌細胞的生長,，盡管西妥昔單抗（一種單克隆抗體藥物）在臨床上可以成功治療肺癌、直腸癌等疾病,，但是在治療GBM這種疾病上卻并不奏效,。
研究者Paul Clark博士表示，西妥昔單抗可以關(guān)閉EGFR的活力并且抑制癌細胞的生長,。但是癌癥干細胞可以通過開啟兩個EGFR家族受體（ERBB2和ERBB3）來補償癌細胞,，使得癌細胞繼續(xù)生長。其中一個受體- ERBB2參與到了某些類型的乳腺癌化療耐藥中,。幸運的是,，另一種被FDA批準的新藥阿帕替尼可以抑制ERBB2的活性以及多重EGFR成員的信號途徑。
這項研究揭示了癌癥干細胞的生長可以被阿帕替尼療法所抑制,，研究者Clark表示,，這是一個好消息，因為這些藥物療法主要是瞄準GBM癌細胞生長過快和逃避傳統(tǒng)的療法,，而且分子靶向藥物對于病人的耐受性較好,，副作用也較小。研究者Kuo最后表示,，目前臨床上使用新藥和其它治療措施治療腦癌的試驗正在進行之中,。
相關(guān)研究成果已經(jīng)于近日刊登在了國際腫瘤學權(quán)威期刊Neoplasia上。（生物谷Bioon.com）
編譯自：Novel Way to Treat Drug-Resistant Brain Tumor Cells
編譯者：T.Shen
doi:10.1596/neo.12432
PMC:
PMID:
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.
