PMID- 20670944
OWN - NLM
STAT- MEDLINE
DCOM- 20110202
LR  - 20211020
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 16
IP  - 18
DP  - 2010 Sep 15
TI  - Molecular analysis of non-small cell lung cancer identifies subsets with 
      different sensitivity to insulin-like growth factor I receptor inhibition.
PG  - 4654-65
LID - 10.1158/1078-0432.CCR-10-0089 [doi]
AB  - PURPOSE: 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. EXPERIMENTAL DESIGN: 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. CONCLUSION: NSCLC comprises molecular subsets 
      with differential sensitivity to IGF-IR inhibition.
CI  - (c)2010 AACR.
FAU - Gualberto, Antonio
AU  - Gualberto A
AD  - Department of Clinical Development and Medical Affairs, Pfizer Oncology, New 
      London, Connecticut, USA. antonio_gualberto@brown.edu
FAU - Dolled-Filhart, Marisa
AU  - Dolled-Filhart M
FAU - Gustavson, Mark
AU  - Gustavson M
FAU - Christiansen, Jason
AU  - Christiansen J
FAU - Wang, Yu-Fen
AU  - Wang YF
FAU - Hixon, Mary L
AU  - Hixon ML
FAU - Reynolds, Jennifer
AU  - Reynolds J
FAU - McDonald, Sandra
AU  - McDonald S
FAU - Ang, Agnes
AU  - Ang A
FAU - Rimm, David L
AU  - Rimm DL
FAU - Langer, Corey J
AU  - Langer CJ
FAU - Blakely, Johnetta
AU  - Blakely J
FAU - Garland, Linda
AU  - Garland L
FAU - Paz-Ares, Luis G
AU  - Paz-Ares LG
FAU - Karp, Daniel D
AU  - Karp DD
FAU - Lee, Adrian V
AU  - Lee AV
LA  - eng
GR  - R01 ES015704-04/ES/NIEHS NIH HHS/United States
GR  - P50CA58183/CA/NCI NIH HHS/United States
GR  - R01 ES015704/ES/NIEHS NIH HHS/United States
GR  - ES015704/ES/NIEHS NIH HHS/United States
GR  - P50 CA058183/CA/NCI NIH HHS/United States
GR  - R01 CA094118/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Retracted Publication
PT  - Validation Study
DEP - 20100729
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hormone Antagonists)
RN  - 0 (Immunoglobulins, Intravenous)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - VE267FC2UB (figitumumab)
SB  - IM
RIN - Clin Cancer Res. 2014 Jun 15;20(12):3358. doi: 10.1158/1078-0432.CCR-14-1118. 
      PMID: 24928947
MH  - Animals
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Antineoplastic Agents/therapeutic use
MH  - Carcinoma, Non-Small-Cell Lung/classification/*diagnosis/*drug therapy/metabolism
MH  - Clinical Trials, Phase II as Topic
MH  - *Drug Resistance, Neoplasm/drug effects
MH  - Female
MH  - Hormone Antagonists/therapeutic use
MH  - Humans
MH  - Immunoglobulins, Intravenous
MH  - Insulin-Like Growth Factor I/*antagonists & inhibitors/immunology
MH  - Male
MH  - Mice
MH  - Molecular Diagnostic Techniques
MH  - NIH 3T3 Cells
MH  - Prognosis
MH  - Retrospective Studies
MH  - Tissue Array Analysis
PMC - PMC2952544
MID - NIHMS226076
EDAT- 2010/07/31 06:00
MHDA- 2011/02/03 06:00
PMCR- 2011/09/15
CRDT- 2010/07/31 06:00
PHST- 2010/07/31 06:00 [entrez]
PHST- 2010/07/31 06:00 [pubmed]
PHST- 2011/02/03 06:00 [medline]
PHST- 2011/09/15 00:00 [pmc-release]
AID - 1078-0432.CCR-10-0089 [pii]
AID - 10.1158/1078-0432.CCR-10-0089 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2010 Sep 15;16(18):4654-65. doi: 10.1158/1078-0432.CCR-10-0089. 
      Epub 2010 Jul 29.