ecular Analysis of Non–Small Cell Lung Cancer Identifies sets with Different Sensitivity to Insulin-like Growth

wnloaded pose: This study aimed to identify molecular determinants of sensitivity of non–small cell lung (NSCLC) to anti–insulin-like growth factor receptor (IGF-IR) therapy. erimental Design: A total of 216 tumor samples were investigated, of which 165 consisted of rettive analyses of banked tissue and an additional 51 were from patients enrolled in a phase II study tumumab, a monoclonal antibody against IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed ed IGF-IR, epidermal growth factor receptor, IGF-II, IGF-IIR, insulin receptor substrate 1 (IRS-1), vimentin, and E-cadherin. Subcellular localization of IRS-1 and phosphorylation levels of mitogented protein kinase and Akt1 were also analyzed. ults: IGF-IR was differentially expressed across histologic subtypes (P = 0.04), with highest levels ed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of ous cell tumors responding to chemotherapy combined with figitumumab (P = 0.008). Because er biomarker/response interaction was observed using classical histologic subtyping, a molecular ach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal componalysis and unsupervised Bayesian clustering identified three NSCLC subsets that resembled the of the epithelial to mesenchymal transition: E-cadherin high/IRS-1 low (epithelial-like), E-cadherin ediate/IRS-1 high (transitional), and E-cadherin low/IRS-1 low (mesenchymal-like). Several marf the IGF-IR pathway were overexpressed in the transitional subset. Furthermore, a higher response the combination of chemotherapy and figitumumab was observed in transitional tumors (71%) ared with those in themesenchymal-like subset (32%; P = 0.03). Only one epithelial-like tumor was fied in the phase II study, suggesting that advanced NSCLC has undergone significant dedifferenat diagnosis. tiation Conclusion: NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition.