Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
Mol Cancer Ther. 2018 Sep;17(9):2049-2059. doi: 10.1158/1535-7163.MCT-17-1163. Epub 2018 Jul 3.
Eph proteins have emerged as critical drivers affecting tumor growth and progression in human malignancies. Our The Cancer Genome Atlas (TCGA) data analysis showed that EphB3, a receptor tyrosine kinase, is frequently coamplified with PIK3CA in head and neck squamous cell carcinoma (HNSCC). We therefore hypothesized that EphB3 amplification plays a protumorigenic role in HNSCC and that and are cooperating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported, because EphB3 knockdown failed to alter HNSCC tumor cell growth or with an orthotopic model. However, responsiveness of EphB3 knockdown tumors to the PI3K inhibitor, BKM120, was significantly decreased in terms of both tumor growth delay and survival. This is correlated with an increase in prosurvival proteins, S6 and BcL-XL, in the EphB3 shRNA tumors treated with BKM120 compared with controls. We further observed that EphB3 knockdown resulted in increased migration and increased gene signature To explain these results, we examined EphB3 phosphorylation levels in HNSCC at baseline. Although total EphB3 levels were high, we found low phospho-EphB3 levels in HNSCCs. Forced EphB3 phosphorylation with an ephrin-B2-Fc fusion protein resulted in decreased HNSCC migration and cell growth, and enhanced response to BKM120 These data collectively indicate that progression of HNSCC selects for low/inhibited EphB3 activity to enhance their survival and migratory abilities and decrease response to PI3K signaling. Therefore, strategies focused on activating EphB3 might be helpful to inhibit tumor growth and enhance sensitivity to PI3K inhibitors in HNSCC. .
Eph 蛋白已成为影响人类恶性肿瘤生长和进展的关键驱动因素。我们的癌症基因组图谱 (TCGA) 数据分析表明，受体酪氨酸激酶 EphB3 在头颈部鳞状细胞癌 (HNSCC) 中与 PIK3CA 经常共扩增。因此，我们假设 EphB3 扩增在 HNSCC 中发挥致癌作用，并且 EphB3 和 PIK3CA 是合作的致癌基因，有助于其发病机制。这一假设并未得到实验支持，因为 EphB3 敲低未能改变 HNSCC 肿瘤细胞的生长或在原位模型中与 EphB3 敲低肿瘤的生长延迟和存活相关。这与 EphB3 shRNA 肿瘤中 BKM120 治疗时存活蛋白 S6 和 BcL-XL 的增加有关。我们进一步观察到 EphB3 敲低导致迁移增加和基因表达谱增加。为了解释这些结果，我们在基线时检查了 HNSCC 中 EphB3 的磷酸化水平。尽管 EphB3 总水平较高，但我们发现 HNSCC 中磷酸化 EphB3 水平较低。用 Ephrin-B2-Fc 融合蛋白强制 EphB3 磷酸化导致 HNSCC 迁移和细胞生长减少，并增强对 BKM120 的反应。这些数据共同表明，HNSCC 的进展选择低/抑制 EphB3 活性以增强其存活和迁移能力，并降低对 PI3K 信号的反应。因此，专注于激活 EphB3 的策略可能有助于抑制肿瘤生长并增强 HNSCC 对 PI3K 抑制剂的敏感性。
