Department of Molecular Biology, Semmelweis University, H-1094 Budapest, Hungary.
MTA-SE Pathobiochemistry Research Group, Semmelweis University, H-1094 Budapest, Hungary.
Int J Mol Sci. 2023 Feb 1;24(3):2782. doi: 10.3390/ijms24032782.
The poor prognosis of head-and-neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable prognostic and predictive markers. The Ras/Raf/MEK/ERK signaling pathway is often activated by overexpressed epidermal growth factor receptor (EGFR) and stimulates the progression of HNSCCs. Our research was performed on three human papillomavirus (HPV)-negative HNSCC-cell lines: Detroit 562, FaDu and SCC25. Changes in cell viability upon EGFR and/or MEK inhibitors were measured by the MTT method. The protein-expression and phosphorylation profiles of the EGFR-initiated signaling pathways were assessed using Western-blot analysis. The EGFR expression and pY1068-EGFR levels were also studied in the patient-derived HNSCC samples. We found significant differences between the sensitivity of the tumor-cell lines used. The SCC25 line was found to be the most sensitive to the MEK inhibitors, possibly due to the lack of feedback Akt activation through EGFR. By contrast, this feedback activation had an important role in the FaDu cells. The observed insensitivity of the Detroit 562 cells to the MEK inhibitors might have been caused by their PIK3CA mutation. Among HNSCC cell lines, EGFR-initiated signaling pathways are particularly versatile. An ERK/EGFR feedback loop can lead to Akt-pathway activation upon MEK inhibition, and it is related not only to increased amounts of EGFR but also to the elevation of pY1068-EGFR levels. The presence of this mechanism may justify the combined application of EGFR and MEK inhibitors.
头颈部鳞状细胞癌（HNSCC）预后较差，部分原因是缺乏可靠的预后和预测标志物。Ras/Raf/MEK/ERK 信号通路通常被过表达的表皮生长因子受体（EGFR）激活，并刺激 HNSCC 的进展。我们的研究是在三种人乳头瘤病毒（HPV）阴性的 HNSCC 细胞系中进行的：底特律 562、FaDu 和 SCC25。通过 MTT 法测量 EGFR 和/或 MEK 抑制剂作用下细胞活力的变化。使用 Western-blot 分析评估 EGFR 起始信号通路的蛋白表达和磷酸化谱。还研究了患者来源的 HNSCC 样本中 EGFR 的表达和 pY1068-EGFR 水平。我们发现使用的肿瘤细胞系的敏感性存在显著差异。发现 SCC25 细胞系对 MEK 抑制剂最敏感，可能是由于缺乏通过 EGFR 的 Akt 激活的反馈。相比之下，这种反馈激活在 FaDu 细胞中起着重要作用。观察到 Detroit 562 细胞对 MEK 抑制剂不敏感，可能是由于其 PIK3CA 突变。在 HNSCC 细胞系中，EGFR 起始的信号通路特别多样化。ERK/EGFR 反馈环可导致 MEK 抑制时 Akt 通路激活，并且不仅与 EGFR 数量增加有关，还与 pY1068-EGFR 水平升高有关。这种机制的存在可能证明 EGFR 和 MEK 抑制剂的联合应用是合理的。
