Insulin-like growth factor 1 receptor mutants are inhibited by figitumumab (CP-751, 871) in vitro

To test the hypothesis that mutant insulin‐like growth factor 1 receptor (IGF‐1R) protein may differentially respond to inhibition by figitumumab (CP‐751, 871), potentially necessitating patient screening, we studied the in vitro efficacy of figitumumab against seven identified non‐synonymous somatic IGF‐1R mutations. The IGF‐1R signaling pathway has been implicated in numerous aspects of tumor biology, and inhibition of this pathway has been shown to provide beneficial anti‐tumor effects. Figitumumab is a fully human monoclonal IgG2 antibody against IGF‐1R that has been shown to block ligand binding, inhibit IGF‐1R tyrosine kinase activity, and induce IGF‐1R down‐modulation. There have been reports in the literature of targeted cancer therapies being affected by somatic mutations within the target of the therapy itself as well as downstream in the signaling cascade. To identify somatic DNA mutations within the IGF1R gene, 46 colon and 46 lung matched normal/tumor sets were screened using a mismatch repair detection method. The screening process identified seven unique mutations in either colon or lung cancer samples that altered the IGFIR coding sequence; 5 in colon and 2 in lung. These mutations were distributed across various domains of the receptor with three located in the extracellular alpha chain and four in the intracellular beta chain. Of the four located in the intracellular beta chain, three were in the tyrosine kinase domain. To study the effects of these mutations on the kinase activity of the receptor and the ability to inhibit the mutant receptors with figitumumab, stable cell lines containing wild‐type and the mutant receptors were created and evaluated by ELISA for down‐regulation of the IGF‐1R protein and IGF‐1R phosphorylation. All seven mutant forms of the protein, as well as wild‐type IGF‐1R were inhibited by figitumumab. Six of the seven mutant proteins maintained dependency on ligand stimulation for kinase activity while one mutant, a glycine to arginine change at amino acid position 1199, lacked kinase activity all together. The results of our experiments suggest that figitumumab effectively inhibited the wild‐type and mutant IGF‐1R receptors in this study and therefore screening of figitumumab patients for these mutations should not be necessary. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B119.