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.
