Department of Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400030, China.
Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
Aging (Albany NY). 2021 Aug 30;13(16):20793-20807. doi: 10.18632/aging.203475.
Apatinib resistance is the main obstacle to the effective treatment of advanced head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate the function of Erb-B2 receptor tyrosine kinase 2 (ERBB2) and stimulator of interferon response cGAMP interactor (STING) in apatinib resistance in HNSCC.
The Cancer Genome Atlas database of HNSCC was used to analyze the relationship between vascular endothelial growth factor receptor 2 (VEGFR2) expression and prognosis. An apatinib resistant (AR) HNSCC cell line was constructed based on the CAL27 cell line. RNA sequencing was performed to explore the differentially expressed mRNAs. Quantitative real-time reverse transcription PCR (qRT-PCR) and western blotting were used to evaluate the expression and phosphorylation level VEGFR2, ERBB2, STING, and related proteins. Apatinib resistance was evaluated by colony formation and cell viability assays. A mouse subcutaneous tumor formation model was established to evaluate the efficiency of combination treatment and vascularization was evaluated by assessing CD31 immunofluorescence.
The expression of VEGFR2 was high in tumor of patients with HNSCC. Western blotting and qRT-PCR revealed that in AR cells, ERBB2 expression was high, whereas the expression of STING was low. Targeted treatment of ERBB2 using lapatinib could attenuate apatinib resistance. Further research confirmed that overexpressing could decrease ERBB2 expression.
STING could sensitize AR cells to apatinib by decreasing ERBB2 expression. The combination of lapatinib or a STING agonist with apatinib ameliorated acquired apatinib resistance in a synergistic manner.
阿帕替尼耐药是晚期头颈部鳞状细胞癌（HNSCC）有效治疗的主要障碍。本研究旨在评估表皮生长因子受体 2（VEGFR2）和干扰素刺激基因 cGAMP 相互作用因子（STING）在 HNSCC 中阿帕替尼耐药中的作用。
利用 HNSCC 的癌症基因组图谱数据库分析血管内皮生长因子受体 2（VEGFR2）表达与预后的关系。基于 CAL27 细胞系构建阿帕替尼耐药（AR）HNSCC 细胞系。进行 RNA 测序以探索差异表达的 mRNAs。采用定量实时逆转录聚合酶链反应（qRT-PCR）和蛋白质印迹法检测 VEGFR2、ERBB2、STING 及相关蛋白的表达和磷酸化水平。通过集落形成和细胞活力测定评估阿帕替尼耐药性。建立小鼠皮下肿瘤形成模型以评估联合治疗的效率，并通过评估 CD31 免疫荧光评估血管生成。
HNSCC 患者肿瘤中 VEGFR2 表达较高。Western blot 和 qRT-PCR 显示，在 AR 细胞中 ERBB2 表达较高，而 STING 表达较低。使用拉帕替尼靶向治疗 ERBB2 可减弱阿帕替尼耐药性。进一步的研究证实，过表达 可降低 ERBB2 表达。
STING 可通过降低 ERBB2 表达使 AR 细胞对阿帕替尼敏感。拉帕替尼或 STING 激动剂与阿帕替尼联合使用可协同改善获得性阿帕替尼耐药。
