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

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.

Automated summary

The poor prognosis of head-and-neck squamous cell carcinoma (HNSCC) is due to the lack of prognostic and predictive markers. The Ras/Raf/MEK/ERK signaling pathway is activated by overexpressed epidermal growth factor receptor (EGFR) and promotes the progression of HNSCCs. Our study investigated the effects of EGFR and MEK inhibitors on HNSCC-cell lines and found variations in sensitivity among different cell lines. The feedback activation of Akt through EGFR played a role in FaDu cells, while the insensitivity of Detroit 562 cells might be due to a PIK3CA mutation. The versatility of EGFR-initiated signaling pathways in HNSCC cell lines justifies the combined application of EGFR and MEK inhibitors.