azd-6244 and Head-and-Neck-Neoplasms

Topics: Adult; Aged; Benzimidazoles; Black or African American; DNA Methylation; Female; Head and Neck Neoplasms; Health Status Disparities; Humans; Male; Middle Aged; Mutation; Squamous Cell Carcinoma of Head and Neck; White People

Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has been a longstanding challenge for head and neck oncologists, and current treatments still have limited efficacy. ERK is aberrantly overexpressed and activated in HNSCC. Herein, we aimed to investigate the cause of the limited therapeutic effect of selumetinib, a selective inhibitor of MEK in HNSCC, as MEK/ERK reactivation inevitably occurs. We assessed the effects of combining selumetinib with fibroblast growth factor receptor 3 (FGFR3) inhibitor (PD173074) on tumor growth. Selumetinib transiently inhibited MAPK signaling and reactivated ERK signaling in HNSCC cells. Rebound in the ERK and Akt pathways in HNSCC cells was accompanied by increased FGFR3 signaling after selumetinib treatment. Feedback activation of FGFR3 was a result of autocrine secretion of the FGF2 ligand. The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib. These results provided rational therapeutic strategies for clinical studies of this subtype of patients that show a poor prognosis with selumetinib. Our data provide a rationale for combining a MEK inhibitor with inhibitors of feedback activation of FGFR3 signaling in HNSCC cells. ERK rebound as a result of the upregulation of FGFR3 and the ligand FGF2 diminished the antitumor effects of selumetinib, which was overcome by combination treatment with the FGFR3 inhibitor.

Topics: Animals; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Fibroblast Growth Factor 2; Head and Neck Neoplasms; Humans; MAP Kinase Signaling System; Mice; Pyrimidines; Receptor, ErbB-3; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

In melanoma, the RAS/RAF/MEK/ERK pathway is frequently activated by mutations in BRAF and NRAS. Selumetinib (AZD6244) is an oral, selective, non-ATP-competitive inhibitor of MEK1/2. Here, we describe a patient with metastatic melanoma (T1N2cM1a) with a BRAF V600E mutation. She is currently being treated with selumetinib 75 mg twice daily in a phase I trial and has shown complete response for the past 4 years. This case report raises questions regarding treatment schedule, treatment duration and management of adverse events.

Topics: Adult; Antineoplastic Agents; Benzimidazoles; Disease-Free Survival; Female; Head and Neck Neoplasms; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Thoracic Neoplasms