Department of Oral Pathology, Howard University College of Dentistry, Washington, DC, USA.
Department of Cancer Center, Howard University College of Dentistry, Washington, DC, USA.
Head Neck. 2021 Jun;43(6):1721-1729. doi: 10.1002/hed.26633. Epub 2021 Feb 3.
Epidermal growth factor receptor (EGFR) overexpression is one of the most notable characteristics in head and neck squamous cell carcinoma (HNSCC). The MAPK kinase (MEK) inhibitor trametinib has shown efficacy to treat HNSCC; however, the molecular mechanism remains unclear.
HNSCC lines, mouse models, Western blot, and flow cytometry were employed to analyze the anticancer effects of trametinib.
The JHU-011, JHU-022, and JHU-029 HNSCC cells with different genetic alterations were highly susceptible to trametinib. Trametinib effectively reduced EGFR expression, which was accompanied by the reduction of pro-survival protein MYC, and the increased expression of a MYC-targeted cyclin-dependent kinase inhibitor p27kip1 and pro-apoptotic protein BIM. Trametinib resulted in G1 arrest of the cells, markedly reduced cell numbers in S phase, and significantly increased apoptosis. In mouse models, trametinib strongly inhibited tumors growth.
The MAPK-ERK signaling inhibition by trametinib may target EGFR and the downstream proteins against HNSCC.
表皮生长因子受体（EGFR）过表达是头颈部鳞状细胞癌（HNSCC）的最显著特征之一。MAPK 激酶（MEK）抑制剂曲美替尼已显示出治疗 HNSCC 的疗效；然而，其分子机制尚不清楚。
采用 HNSCC 细胞系、小鼠模型、Western blot 和流式细胞术分析曲美替尼的抗癌作用。
具有不同遗传改变的 JHU-011、JHU-022 和 JHU-029 HNSCC 细胞对曲美替尼高度敏感。曲美替尼可有效降低 EGFR 表达，同时降低生存蛋白 MYC 的表达，并增加 MYC 靶向细胞周期蛋白依赖性激酶抑制剂 p27kip1 和促凋亡蛋白 BIM 的表达。曲美替尼导致细胞 G1 期停滞，明显减少 S 期细胞数量，并显著增加细胞凋亡。在小鼠模型中，曲美替尼强烈抑制肿瘤生长。
曲美替尼对 MAPK-ERK 信号的抑制可能针对 EGFR 及其下游蛋白治疗 HNSCC。
