Abstract LB-303: Anti-IGF1R therapy with dalotuzumab is efficacious in pre-clinical models of erlotinib refractory NSCLC
Authors: Xu Youyuan , Jha Sharda , Sykes Kara , Paweletz Cloud P. , Nebozhyn Michael , Feldman Igor , Loboda andrey , Reilly john , Winter Christopher , Zhang Theresa , Sathyanarayanan Sriram 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR) is expressed in a majority of non-small cell lung carcinomas (NSCLC) and it has been an attractive target for the development of therapeutic agents. The small-molecule EGFR tyrosine kinase inhibitors (TKI), including gefitinib and erlotinib, are currently used in the treatment of late stage NSCLC. Activating mutations in the oncogene KRAS has been associated with resistance to EGFR targeted therapy. Cross-talk between EGFR and insulin like growth factor receptor (IGF1R) has been reported. MK-0646 (dalotuzumab), a monoclonal antibody targeting IGF1R is currently being developed for the treatment of various cancers. Pre-clinical studies suggest that response to EGFR inhibitors can be substantially increased by combining with an IGF1R inhibitor such as MK-0646, a hypothesis currently being tested in clinical studies. In this study, sensitivity to MK-0646 or erlotinib or their combination was compared in a panel of NSCLC cell lines harboring wild type or activating mutations in KRAS. Erlotinib sensitivity was observed in 3/26 (12%) cell lines, all of which harbored wild type KRAS. In contrast, MK-0646 sensitivity was observed in 4/26 (15%), two of which harbor activating mutations in RAS. Sensitivity to erlotinib/MK-0646 combination was observed in 11/26 (42%) cell lines. Activating mutations in KRAS did not confer resistance to MK-0646 treatment. To identify predictive biomarkers that would enrich responders to MK-0646 therapy, gene expression profiling and reverse phase protein array were performed in this panel of NSCLC cell lines. Analysis of reverse-phase protein arrays identified IGF1R levels as a predictive marker of response to MK-0646. In contrast, ERBB3 levels and a gene signature of epithelial mesenchymal transition (EMT) were predictive of sensitivity to erlotinib, but not response to MK-0646. Sensitivity to MK-0646 was observed in primary human tumors propagated in mice or cell line xenografts harboring activating mutations in KRAS. The activity of MK-0646 in KRAS mutant NSCLC models is associated with inhibition of the PI3K pathway and subsequent down-regulation of the “Growth factor associated gene-expression signature” (GFS). The parallel RAS-MAPK pathway was not significantly modulated by MK-0646 treatment. The results suggest that patients with high levels of IGF1R expression, independent of KRAS status, will benefit from MK-0646 therapy. Growing number of studies suggest that EGFR inhibitors is not efficacious in patients harboring tumors with activating mutations in KRAS. MK-0646 therapy may overcome this resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-303.