| 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
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