Molecular Analysis of Non-Small Cell Lung Cancer Identifies Subsets with Different Sensitivity to Insulin-like Growth Factor I Receptor Inhibition (Retracted article. See vol. 20, pg. 3358, 2014)

作者：Gualberto Antonio^*; Dolled Filhart Marisa; Gustavson Mark; Christiansen Jason; Wang Yu Fen; Hixon Mary L; Reynolds Jennifer; McDonald Sandra; Ang Agnes; Rimm David L; Langer Corey J; Blakely Johnetta; Garland Linda; Paz Ares Luis G; Karp Daniel D; Lee Adrian V

来源：Clinical Cancer Research, 2010, 16(18): 4654-4665.

DOI：10.1158/1078-0432.CCR-10-0089

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 themesenchymal-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. Clin Cancer Res; 16(18); 4654-65.

• 出版日期2010-9-15