High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-lGF-1R antibody (R1507) Journal Article

Authors: Gong, Y.; Yao, E.; Shen, R.; Goel, A.; Arcila, M.; Teruya-Feldstein, J.; Zakowski, M. F.; Frankel, S.; Peifer, M.; Thomas, R. K.; Ladanyi, M.; Pao, W.
Article Title: High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-lGF-1R antibody (R1507)
Abstract: Background: The IGF receptor type 1 (IGF-1R) pathway is frequently deregulated in human tumors and has become a target of interest for anti-cancer therapy. Methodology/Principal Findings: We used a panel of 22 non-small cell lung cancer (NSCLC) cell lines to investigate predictive biomarkers of response to R1507, a fully-humanized anti-IGF-1R monoclonal antibody (Ab; Roche). 5 lines were moderately sensitive (25-50% growth inhibition) to R1507 alone. While levels of phospho-IGF-1R did not correlate with drug sensitivity, 4 out of 5 sensitive lines displayed high levels of total IGF-1R versus 1 out of 17 resistant lines (p = 0.003, Fisher's Exact). Sensitive lines also harbored higher copy numbers of IGF-1R as assessed by independent SNP array analysis. Addition of erlotinib or paclitaxel to R1507 led to further growth inhibition in sensitive but not resistant lines. In one EGFR mutant lung adenocarcinoma cell line (11-18), R1507 and erlotinib co-treatment induced apoptosis, whereas treatment with either drug alone induced only cell cycle arrest. Apoptosis was mediated, in part, by the survival-related AKT pathway. Additionally, immunohistochemical (IHC) staining of total IGF-1R with an anti-total IGF-1R Ab (G11;Ventana) was performed on tissue microarrays (TMAs) containing 270 independent NSCLC tumor samples. Staining intensity was scored on a scale of 0 to 3+. 39.3% of tumors showed medium to high IGF-1R IHC staining (scores of 2+ or 3+, respectively), while 16.7% had scores of 3+. Conclusions/Significance: In NSCLC cell lines, high levels of total IGF-1R are associated with moderate sensitivity to R1507. These results suggest a possible enrichment strategy for clinical trials with anti-IGF-1R therapy. © 2009 Gong et al.
Keywords: immunohistochemistry; protein kinase b; controlled study; unclassified drug; human cell; single nucleotide polymorphism; polymorphism, single nucleotide; erlotinib; antineoplastic agents; drug targeting; paclitaxel; antineoplastic agent; adenocarcinoma; metabolism; cell survival; apoptosis; gene expression; gene expression profiling; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; tumor markers, biological; small interfering rna; rna, small interfering; in vitro study; cell line, tumor; tumor marker; monoclonal antibody; r 1507; somatomedin c receptor; receptor, igf type 1; lung tumor; gene expression regulation; cancer inhibition; gene number; gene expression regulation, neoplastic; immunology; chemistry; oligonucleotide array sequence analysis; nucleotide sequence; tumor cell line; scoring system; cell cycle arrest; dna microarray; gene silencing; antibodies; tissue microarray; drug sensitivity; somatomedin receptor monoclonal antibody; antibody
Journal Title: PLoS ONE
Volume: 4
Issue: 10
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2009-10-06
Start Page: e7273
Language: English
DOI: 10.1371/journal.pone.0007273
PUBMED: 19806209
PROVIDER: scopus
PMCID: PMC2752171
Notes: --- - "Cited By (since 1996): 8" - "Export Date: 30 November 2010" - "Art. No.: e7273" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Julie T Feldstein
    292 Feldstein
  2. Ronglai Shen
    144 Shen
  3. William Pao
    141 Pao
  4. Marc Ladanyi
    1052 Ladanyi
  5. Maureen F Zakowski
    287 Zakowski
  6. Yixuan Gong
    15 Gong
  7. Maria Eugenia Arcila
    466 Arcila
  8. Aviva J Goel
    7 Goel
  9. Evelyn Sheau-Yun Yao
    8 Yao