ERBB3、IGF1R和TGFBR2的表达与胶质母细胞瘤中的PDGFR表达相关，并参与胶质母细胞瘤细胞对PDGFR抑制剂的耐药性。
ERBB3, IGF1R, and TGFBR2 expression correlate with PDGFR expression in glioblastoma and participate in PDGFR inhibitor resistance of glioblastoma cells.
作者信息
Song Kang, Yuan Ye, Lin Yong, Wang Yan-Xia, Zhou Jie, Gai Qu-Jing, Zhang Lin, Mao Min, Yao Xiao-Xue, Qin Yan, Lu Hui-Min, Zhang Xiang, Cui You-Hong, Bian Xiu-Wu, Zhang Xia, Wang Yan
机构信息
Department of Pathology, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China.
Key Laboratory of Tumor Immunology and Pathology of Ministry of Education Chongqing 400038, China.
出版信息
Am J Cancer Res. 2018 May 1;8(5):792-809. eCollection 2018.
Glioma, the most prevalent malignancy in brain, is classified into four grades (I, II, III, and IV), and grade IV glioma is also known as glioblastoma multiforme (GBM). Aberrant activation of receptor tyrosine kinases (RTKs), including platelet-derived growth factor receptor (PDGFR), are frequently observed in glioma. Accumulating evidence suggests that PDGFR plays critical roles during glioma development and progression and is a promising drug target for GBM therapy. However, PDGFR inhibitor (PDGFRi) has failed in clinical trials, at least partially, due to the activation of other RTKs, which compensates for PDGFR inhibition and renders tumor cells resistance to PDGFRi. Therefore, identifying the RTKs responsible for PDGFRi resistance might provide new therapeutic targets to synergetically enhance the efficacy of PDGFRi. In this study, we analyzed the TCGA glioma database and found that the mRNA expressions of three RTKs, i.e. ERBB3, IGF1R, and TGFBR2, were positively correlated with that of PDGFR. Co-immunoprecipitation assay indicated novel interactions between the three RTKs and PDGFR in GBM cells. Moreover, concurrent expression of PDGFR with ERBB3, IGF1R, or TGFBR2 in GBM cells attenuated the toxicity of PDGFRi and maintained the activation of PDGFR downstream targets under the existence of PDGFRi. Thus, ERBB3, IGF1R, and TGFBR2 might participate in PDGFRi resistance of GBM cells. Consistent with this notion, combination of PDGFRi with inhibitor targeting either ERBB3 or IGF1R more potently suppressed the growth of GBM cells than each inhibitor alone. The positive correlations of PDGFR with ERBB3, IGF1R, and TGFBR2 were further confirmed in 66 GBM patient samples. Intriguingly, survival analysis showed that ERBB3 predicted poor prognosis in GBM patients with high PDGFRA expression. Altogether, our work herein suggested that ERBB3, IGF1R, and TGFBR2 were responsible for PDGFRi resistance and revealed that ERBB3 acted as potential prognostic marker and therapeutic target for GBM with high PDGFRA expression.
胶质瘤是脑部最常见的恶性肿瘤，分为四个级别（I、II、III和IV级），IV级胶质瘤也被称为多形性胶质母细胞瘤（GBM）。在胶质瘤中经常观察到受体酪氨酸激酶（RTK）的异常激活，包括血小板衍生生长因子受体（PDGFR）。越来越多的证据表明，PDGFR在胶质瘤的发生和发展过程中起关键作用，是GBM治疗中一个有前景的药物靶点。然而，PDGFR抑制剂（PDGFRi）在临床试验中失败了，至少部分原因是其他RTK的激活，这补偿了PDGFR的抑制作用，并使肿瘤细胞对PDGFRi产生抗性。因此，鉴定导致PDGFRi抗性的RTK可能会提供新的治疗靶点，以协同增强PDGFRi的疗效。在本研究中，我们分析了TCGA胶质瘤数据库，发现三种RTK，即ERBB3、IGF1R和TGFBR2的mRNA表达与PDGFR的表达呈正相关。免疫共沉淀分析表明，在GBM细胞中这三种RTK与PDGFR之间存在新的相互作用。此外，在GBM细胞中PDGFR与ERBB3、IGF1R或TGFBR2的共表达减弱了PDGFRi的毒性，并在存在PDGFRi的情况下维持了PDGFR下游靶点的激活。因此，ERBB3、IGF1R和TGFBR2可能参与了GBM细胞对PDGFRi的抗性。与此观点一致的是，与单独使用每种抑制剂相比，PDGFRi与靶向ERBB3或IGF1R的抑制剂联合使用更有效地抑制了GBM细胞的生长。在66例GBM患者样本中进一步证实了PDGFR与ERBB3、IGF1R和TGFBR2的正相关。有趣的是，生存分析表明，ERBB3预测PDGFRA高表达的GBM患者预后不良。总之，我们的工作表明ERBB3、IGF1R和TGFBR2是导致PDGFRi抗性的原因，并揭示ERBB3是PDGFRA高表达的GBM的潜在预后标志物和治疗靶点。
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