FGFR-mediated reactivation of ERK signaling contributes to insensitivity of head and neck squamous cancer to MEK inhibition

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S129-S129
• Main Authors: Yang, Y.J, Na, H.J, Ban, M.J, Byeon, H.K, Koh, Y.W, Kim, J.W
• Format: Article
• Language: English
• Subjects: Activation; AKT protein; Anticancer properties; Antitumor activity; Autocrine signalling; Cancer; Extracellular signal-regulated kinase; Feedback; Fibroblast growth factor 2; Fibroblast growth factor receptors; Head; Head & neck cancer; Head and neck carcinoma; Hematology, Oncology and Palliative Medicine; Inhibitors; Ligands; MAP kinase; Medical prognosis; MEK inhibitors; Mesenchyme; Metastases; Pathology; Protease; Secretion; Serine; Serine proteinase; Squamous cell carcinoma; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32985-9

Treatments (or recurrent or meiastatic head and neck squamous cell carcinoma (HNSCC) have limited efficacy. The extracellular signal-regulated kinase (ERK) expression and activation exhibits aberrant overexpression in human head and neck squamous cell carcinomas (HNSCC). Here, we aimed to investigate the cause of the limited therapeutic effect of MEK inhibitor in head and neck squamous cell carcinoma (HNSCC) because MEK/ERK reactivation has been shown inevitably occurs. We assessed the effects combining seletinib with FGFR3 inhibitor (PD173074) on tumor growth. In addition, we analyzed the level of EMT-related genes and protease to determine the pathological events such as tumor invasion and metastasis. We showed that selumetinib is inhibited MAPK signaling transiently in head and neck cancer cells. The rebound in ERK and AKT pathway in head and neck cancer cells is accompanied by increased phospho-FGFR3 signaling after treatment of selumetinib. Feedback activation of FGFR3 is due to an autocrine secretion of FGF2 ligand. The FGFR3 inhibitor PD173074 prevents the MAPK rebound and sensitizes a responding of head and neck cancer cells to selumetinib. In addition, we investigated that rapid feedback activation of FGFR3 regulates the expression of epithelial to mesenchymal transition (EMT) markers and uPA serine protease, which resulted in high migratory potentials in tumor invasion. These results provide rational therapeutic strategies for clinical studies in this poor prognosis subtype of selumetinib. Our data determined that a rationale for combining MEK inhibitor with inhibitors of feedback activation of FGFR3 signaling in head and neck cancer cells. ERK rebound due to up regulation of FGFR3 and the ligand FGF2 diminished the antitumor effect of selumetinib, which is overcome by combination with FGFR3 inhibitor.