MEK Is a Potential Indirect Target in Subtypes of Head and Neck Cancers

• Published in: International journal of molecular sciences 2023-02, Vol.24 (3), p.2782
• Main Authors: Gurbi, Bianka, Brauswetter, Diána, Pénzes, Kinga, Varga, Attila, Krenács, Tibor, Dános, Kornél, Birtalan, Ede, Tamás, László, Csala, Miklós
• Format: Article
• Language: English
• Subjects: AKT protein; Alcohol; Apoptosis; Biomarkers; Cancer therapies; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell viability; Cells; Chemotherapy; Drug resistance; Epidermal growth factor; epidermal growth factor receptor; Epidermal growth factor receptors; ErbB Receptors - metabolism; Feedback; feedback loop; Feedback loops; Growth factors; Head & neck cancer; Head and Neck Neoplasms - genetics; head-and-neck cancer; Human papillomavirus; Humans; Inhibitors; Kinases; Localization; Medical prognosis; MEK; MEK inhibitors; Metastasis; Mitogen-Activated Protein Kinase Kinases; Mutation; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt; Radiation therapy; Raf protein; Signal transduction; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Tumor cell lines; Tumorigenesis; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.