Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition
Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition
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DOI：
10.1596/neo.12432
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发表时间：
2012-05-01
期刊：
影响因子：
4.8
通讯作者：
Kuo, John S.
中科院分区：
文献类型：
--
作者：
Clark, Paul A.;Iida, Mari;Kuo, John S.
表皮生长因子受体（EGFR）信号传导与胶质母细胞瘤（GBM）肿瘤发生密切相关。然而，靶向EGFR的分子药物在临床试验中表现出最小的疗效，表明存在GBM耐药机制。具有干细胞样特性（CSC）的GBM细胞在肿瘤起始时是高效的，并且表现出治疗抗性。在这项研究中，GBM CSC细胞系在EGF从细胞培养基中撤出后显示出球体形成和肿瘤起始能力，而正常神经干细胞在EGF撤出后迅速死亡。在剥夺EGFR信号（EGF剥夺或西妥昔单抗抑制）的GBM CSC中观察到相关ERBB家族受体（ERBB 2和ERBB 3）的补偿性激活，表明EGFR靶向治疗的内在GBM抗性机制。在集落形成试验中，与西妥昔单抗介导的EGFR特异性抑制相比，拉帕替尼对EGFR和ERBB 2的双重抑制显著降低了GBM增殖。拉帕替尼抑制下游ERBB信号传导组分（AKT、ERK 1/2）的磷酸化和GBM CSC增殖。总的来说，这些发现表明GBM对EGFR抑制剂的治疗抗性可以通过EGFR相关家族成员（ERBB 2，ERBB 3）的补偿性激活来解释，从而使GBM CSC增殖，因此可能需要同时阻断多个ERBB家族成员才能实现更有效的GBM治疗。Neoplasia（2012）14，420-428
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 (CSCs) 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 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. Neoplasia (2012) 14, 420-428