Premium
HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells
Author(s) -
Hah J. Hun,
Zhao Mei,
Pickering Curtis R.,
Frederick Mitchell J.,
Andrews Genevieve A.,
Jasser Samar A.,
Fooshee David R.,
Milas Zvonimir L.,
Galer Chad,
Sano Daisuke,
William William N.,
Kim Edward,
Heymach John,
Byers Lauren A.,
Papadimitrakopoulou Vali,
Myers Jeffrey N.
Publication year - 2014
Publication title -
head and neck
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 127
eISSN - 1097-0347
pISSN - 1043-3074
DOI - 10.1002/hed.23499
Subject(s) - erlotinib , hras , cancer research , epidermal growth factor receptor , head and neck squamous cell carcinoma , cetuximab , kras , erlotinib hydrochloride , biology , cancer , mutation , head and neck cancer , genetics , gene , colorectal cancer
Abstract Background The purpose of this study 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 methyl thiazolyl‐tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated. Results All 7 cell lines were wild‐type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib‐resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (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. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1547–1554, 2014