InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.
InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.
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DOI：
10.1158/1078-0432.ccr-15-1677
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Ma Y;Tang N;Thompson RC;Mobley BC;Clark SW;Sarkaria JN;Wang J
表皮生长因子受体(EGFR)的异常激活是胶质母细胞瘤的一个特征。然而，EGFR抑制剂在胶质母细胞瘤中表现出最好的适度疗效。这与在EGFR突变肺癌中观察到的结果形成鲜明对比。我们研究了功能冗余受体酪氨酸激酶(RTK)的激活是否会导致胶质母细胞瘤对EGFR抑制剂的抵抗。我们收集了一组患者来源的胶质母细胞瘤异种移植(PDX)系，它们在连续的异种移植和组织培养中保持了野生型或突变型EGFR的表达。利用这个生理相关的平台，我们测试了几种RTK配体保护胶质母细胞瘤细胞免受EGFR抑制剂吉非替尼的影响的能力。在筛选结果的基础上，我们进一步发展了联合靶向EGFR和胰岛素受体(InsR)/胰岛素样生长因子1受体(IGF1R)的联合治疗。胰岛素和IGF1在大多数EGFR依赖的PDX株中诱导了对吉非替尼的显著保护作用，但有一个例外，即不表达InsR或IGF1R。阻断InsR/IGF1R通路可协同提高对吉非替尼或达科米替尼的敏感性。单独使用吉非替尼可有效抑制EGFR活性及其下游的MEK/ERK信号通路。然而，抑制AKT和诱导细胞凋亡需要同时抑制EGFR和InsR/IGF1R。联合使用吉非替尼和OSI-906，一种双重的InsR/IGF1R抑制剂，比单独使用任何一种药物治疗皮下胶质母细胞瘤异种移植瘤更有效。我们的结果表明，InsR/IGF1R通路的激活通过AKT调节使EGFR依赖的胶质母细胞瘤对EGFR抑制剂产生抵抗。同时阻断这两条通路有望治疗EGFR依赖型胶质母细胞瘤。
Aberrant activation of epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast to the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma. We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy co-targeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R). Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not expression InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors. Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.