The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Division of Radiooncology-Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mol Oncol. 2023 Dec;17(12):2618-2636. doi: 10.1002/1878-0261.13500. Epub 2023 Aug 31.
Blocking the mitogen-activated protein kinase (MAPK) pathway with the MEK1/2 inhibitor trametinib has produced promising results in patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that trametinib treatment leads to overexpression and activation of the epidermal growth factor receptor (EGFR) in HNSCC cell lines and patient-derived xenografts. Knockdown of EGFR improved trametinib treatment efficacy both in vitro and in vivo. Mechanistically, we demonstrated that trametinib-induced EGFR overexpression hyperactivates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In vitro, blocking the PI3K pathway with GDC-0941 (pictilisib), or BYL719 (alpelisib), prevented AKT pathway hyperactivation and enhanced the efficacy of trametinib in a synergistic manner. In vivo, a combination of trametinib and BYL719 showed superior antitumor efficacy vs. the single agents, leading to tumor growth arrest. We confirmed our findings in a syngeneic murine head and neck cancer cell line in vitro and in vivo. Taken together, our findings show that trametinib treatment induces hyperactivation of EGFR/PI3K/AKT; thus, blocking of the EGFR/PI3K pathway is required to improve trametinib efficacy in HNSCC.
阻断丝裂原活化蛋白激酶（MAPK）通路的 MEK1/2 抑制剂曲美替尼（trametinib）在头颈部鳞状细胞癌（HNSCC）患者中已取得了令人鼓舞的效果。在本研究中，我们发现曲美替尼治疗可导致 HNSCC 细胞系和患者来源的异种移植物中表皮生长因子受体（EGFR）的过表达和激活。EGFR 的敲低可提高曲美替尼在体外和体内的治疗效果。从机制上讲，我们证明曲美替尼诱导的 EGFR 过表达可过度激活磷脂酰肌醇 3-激酶（PI3K）/AKT 通路。在体外，用 GDC-0941（pictilisib）或 BYL719（alpelisib）阻断 PI3K 通路可防止 AKT 通路过度激活，并以协同方式增强曲美替尼的疗效。在体内，曲美替尼和 BYL719 的联合用药显示出比单一药物更好的抗肿瘤疗效，导致肿瘤生长停滞。我们在体外和体内证实了我们在同源性小鼠头颈部癌细胞系中的发现。综上所述，我们的研究结果表明，曲美替尼治疗可诱导 EGFR/PI3K/AKT 的过度激活；因此，阻断 EGFR/PI3K 通路对于提高曲美替尼在 HNSCC 中的疗效是必需的。
