Abstract
Purpose: 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.Method: 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.Result: 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 STING could decrease ERBB2 expression.Conclusion: 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.
Highlights
Head and neck squamous cell carcinoma (HNSCC), as one of the most common malignant carcinomas, has a poor prognosis, as indicated by its high recurrence rate and metastasis risk
According to the analysis of the TGCA-HNSC dataset, vascular endothelial growth factor receptor 2 (VEGFR2) expression was increased in cancer tissue compared with that in normal tissue. (Supplementary Figure 1A)
VEGFR2 expression was lower in HN6 cells than in HN30 and CAL27 cells (Figure 1A, 1B)
Summary
Head and neck squamous cell carcinoma (HNSCC), as one of the most common malignant carcinomas, has a poor prognosis, as indicated by its high recurrence rate and metastasis risk. The 5-year overall survival (OS) of patients with HNSCC is 40–50%, while that of patients with advanced stage disease is 30–40% [1, 2]. Local and distant tumor recurrence are the main causes of death in patients with locally advanced HNSCC. Angiogenesis is important in pathological conditions, for example in accelerating the growth, progression, and metastasis of tumors [3, 4]. Various pro-angiogenic signaling pathways drive angiogenesis, among which the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway is the most important [5, 6]
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