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HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells.

By: J Hun Hah, Mei Zhao, Curtis R Pickering, Mitchell J Frederick, Genevieve A Andrews, Samar A Jasser, David R Fooshee, Zvonimir L Milas, Chad Galer, Daisuke Sano, William N William, Edward Kim, John Heymach, Lauren A Byers, Vali Papadimitrakopoulou, Jeffrey N Myers

Departments of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Otolaryngology-Head and Neck Surgery, Seoul National University Hospital and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
2013-3-21; doi: 10.1002/hed.23499

Abstract

Background: This was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance. Methods: Erlotinib sensitivity was determined by MTT assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated. Results: All seven cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, one erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Down regulation of HRAS expression by siRNA or shRNA in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib. Conclusion: Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line. Head Neck, 2013.