Data from Inhibition of Insulin-Like Growth Factor 1 Receptor by CP-751,871 Radiosensitizes Non–Small Cell Lung Cancer Cells

Abstract

<div>Abstract<p><b>Purpose:</b> Therapeutic strategies that target the insulin-like growth factor I receptor (IGF-1R) hold promise for a wide variety of cancers. We have now investigated the effect of CP-751,871, a fully human monoclonal antibody specific for IGF-IR, on the sensitivity of human non–small cell lung cancer (NSCLC) cell lines to radiation.</p><p><b>Experimental Design:</b> The radiosensitizing effect of CP-751,871 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced damage was evaluated by immunofluorescence analysis of the histone γ-H2AX and Rad51.</p><p><b>Results:</b> A clonogenic survival assay revealed that CP-751,871 increased the sensitivity of NSCLC cells to radiation <i>in vitro</i>. CP-751,871 inhibited radiation-induced IGF-IR signaling, and potentiated the radiation-induced increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of the histone γ-H2AX and Rad51 also showed that CP-751,871 inhibited the repair of radiation-induced DNA double-strand breaks. Finally, combination therapy with CP-751,871 and radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone.</p><p><b>Conclusions:</b> These results show that CP-751,871 sensitizes NSCLC cells to radiation both <i>in vitro</i> and <i>in vivo</i>, and that this effect of CP-751,871 is likely attributable to the inhibition of DNA repair and enhancement of apoptosis that result from attenuation of IGF-IR signaling. Combined treatment with CP-751,871 and radiation thus warrants further investigation in clinical trials as a potential anticancer strategy. (Clin Cancer Res 2009;15(16):5117–25)</p></div>