Constitutively active Harvey Ras confers resistance to epidermal growth factor receptor-targeted therapy with cetuximab and gefitinib

Cancer Lett. 2011 Jul 1;306(1):85-91. doi: 10.1016/j.canlet.2011.02.035. Epub 2011 Mar 15.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Squamous Cell / metabolism
  • Cell Line, Tumor
  • Cetuximab
  • Drug Resistance, Neoplasm
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gefitinib
  • Genes, ras / genetics*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Models, Biological
  • Phosphorylation
  • Quinazolines / pharmacology*
  • Vulvar Neoplasms / metabolism
  • ras Proteins / metabolism*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Quinazolines
  • Epidermal Growth Factor
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins
  • Cetuximab
  • Gefitinib