title: Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition.
abstract: OBJECTIVE
  This study aimed to identify molecular determinants of sensitivity of non-small cell lung cancer (NSCLC) to anti-insulin-like growth factor receptor (IGF-IR) therapy.
  
  
  METHODS
  A total of 216 tumor samples were investigated, of which 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase II study of figitumumab, a monoclonal antibody against IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, epidermal growth factor receptor, IGF-II, IGF-IIR, insulin receptor substrate 1 (IRS-1), IRS-2, vimentin, and E-cadherin. Subcellular localization of IRS-1 and phosphorylation levels of mitogen-activated protein kinase and Akt1 were also analyzed.
  
  
  RESULTS
  IGF-IR was differentially expressed across histologic subtypes (P = 0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with figitumumab (P = 0.008). Because no other biomarker/response interaction was observed using classical histologic subtyping, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified three NSCLC subsets that resembled the steps of the epithelial to mesenchymal transition: E-cadherin high/IRS-1 low (epithelial-like), E-cadherin intermediate/IRS-1 high (transitional), and E-cadherin low/IRS-1 low (mesenchymal-like). Several markers of the IGF-IR pathway were overexpressed in the transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and figitumumab was observed in transitional tumors (71%) compared with those in the mesenchymal-like subset (32%; P = 0.03). Only one epithelial-like tumor was identified in the phase II study, suggesting that advanced NSCLC has undergone significant dedifferentiation at diagnosis.
  
  
  CONCLUSIONS
  NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition.
authors.affiliation: Department of Clinical Development and Medical Affairs, Pfizer Oncology, New London, Connecticut, USA. antonio_gualberto@brown.edu
authors.forename: Antonio
authors.initials: A
authors.lastname: Gualberto
authors.forename: Marisa
authors.initials: M
authors.lastname: Dolled-Filhart
authors.forename: Mark
authors.initials: M
authors.lastname: Gustavson
authors.forename: Jason
authors.initials: J
authors.lastname: Christiansen
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Wang
authors.forename: Mary L
authors.initials: ML
authors.lastname: Hixon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reynolds
authors.forename: Sandra
authors.initials: S
authors.lastname: McDonald
authors.forename: Agnes
authors.initials: A
authors.lastname: Ang
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.forename: Johnetta
authors.initials: J
authors.lastname: Blakely
authors.forename: Linda
authors.initials: L
authors.lastname: Garland
authors.forename: Luis G
authors.initials: LG
authors.lastname: Paz-Ares
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Karp
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006727:Hormone Antagonists / Q000627:therapeutic use; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D051379:Mice; D025202:Molecular Diagnostic Techniques; D041681:NIH 3T3 Cells; D011379:Prognosis; D012189:Retrospective Studies; D046888:Tissue Array Analysis
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006727:Hormone Antagonists; D016756:Immunoglobulins, Intravenous; D007334:Insulin-Like Growth Factor I; C525021:figitumumab