title: Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors.
abstract: BACKGROUND
  Most patients with nonsmall cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The authors investigated the involvement of insulinlike growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF-1R TKIs.
  
  
  METHODS
  Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in an NSCLC tissue microarray. The authors analyzed the antitumor effects of an IGF-1R TKI (PQIP or OSI-906), either alone or in combination with a small-molecular inhibitor (PD98059 or U0126) or with siRNA targeting K-Ras or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K-Ras mutations.
  
  
  RESULTS
  pIGF-1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant K-Ras, and wild-type (WT) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NSCLC cells with WT EGFR and WT K-Ras but not in those with mutations in these genes. Introduction of mutant K-Ras attenuated the effects of IGF-1R TKIs on NSCLC cells expressing WT K-Ras. Conversely, inactivation of MEK restored sensitivity to IGF-TKIs in cells carrying mutant K-Ras.
  
  
  CONCLUSIONS
  The mutation status of both EGFR and K-Ras could be a predictive marker of response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF-1R TKIs.
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Bryan
authors.initials: B
authors.lastname: Hennessy
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Bonnie
authors.initials: B
authors.lastname: Glisson
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012907:Smoking / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases