title: Constitutively active Harvey Ras confers resistance to epidermal growth factor receptor-targeted therapy with cetuximab and gefitinib.
abstract: Kirsten Ras (K-Ras) mutations have been implicated as a key predictive marker of resistance to therapies targeting the epidermal growth factor receptor (EGFR). To determine whether Harvey Ras (H-Ras) mutations also can confer resistance to EGFR-targeted therapy, we expressed a constitutively active H-Ras (Ras G12V) in A431 human vulvar squamous carcinoma cells. Compared with corresponding control cells, A431-Ras cells exhibited marked resistance to the EGFR inhibitors cetuximab and gefitinib, reducing inhibition of Akt and Erk phosphorylation, inhibition of HIF-1α expression and transcriptional activity, and antitumor effects in vitro and in vivo. Our data indicate that constitutively active H-Ras can also confer resistance to anti-EGFR therapy in cancer cells.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
authors.forename: Rodney B
authors.initials: RB
authors.lastname: Luwor
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Xinqun
authors.initials: X
authors.lastname: Li
authors.forename: Ke
authors.initials: K
authors.lastname: Liang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D014846:Vulvar Neoplasms / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D000068818:Cetuximab; D000077156:Gefitinib