Abstract 5638: Preclinical evidence supporting cotargeting insulin-like growth factor receptor (IGF-1R) and Src in non-small cell lung cancer.

Abstract

Abstract The antitumor efficacy of IGF-1R targeting agents (TKIs or antibodies) has been evaluated in recent clinical trials, but the effect has been found to be marginal and limited. Since it has been suggested that IGF-1R and Src signaling pathways cooperate with each other in the proliferation and survival of cancer cells, we investigated the role of Src in the resistance to the IGF-1R TKI and further suggested the rationale of co-targeting of IGF-1R and Src in the treatment of NSCLC. We examined Src-mediated regulation of IGF-1R activation and assessed the effect of the combined treatment with an IGF-1R TKI and a Src inhibitor on the proliferation, survival, and signaling changes in human NSCLC cells and NSCLC xenografts in nude mice. In addition, expressions of the IGF-1R signaling axis were evaluated in tissue microarrays of NSCLC from two independent databases (N=352, and 353, respectively) and correlated with clinicopathologic characteristics and patient survival. We found co-activation of IGF-1R and Src in various NSCLC cells and modulation of IGF-1R signaling by overexpression or knockdown of Src. Combined blockade of IGF-1R and Src resulted in the suppression of cell proliferation, induction of apoptosis, inhibition of signaling responsible for cell survival and proliferation, and tumor growth in vivo. In human tissue samples, p-IGF-1R/IR, IGF-1R, and pSrc expressions were significantly associated with squamous cell carcinoma (SCC) in both TMAs. pIGF-1R/IR and pSrc had strong positive correlation with each other (P<.0001 and P<.0001, respectively). The expression of pSrc serves as a predictor of poor survival in these patients by multivariate analysis in patients with adenocarcinoma. Our data suggest that Src may play an important role in the resistance of a small molecule inhibitor targeting IGF-1R, and IGF-1R and Src are activated in NSCLC patients and thus should be investigated as therapeutic targets in NSCLC patients. Further studies would be necessary to examine the efficacy of combined treatment targeting IGF-1R and Src in NSCLC patients. Citation Format: Jin-Soo Kim, Hye-Young Min, Hye Jeong Yun, Hyun-Ji Jang, Edward S. Kim, Diane Liu, J. Jack Lee, Carmen Behrens, Scott M. Lippman, Waun Ki Hong, Ignacio I. Wistuba, Ho-Young Lee. Preclinical evidence supporting cotargeting insulin-like growth factor receptor (IGF-1R) and Src in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5638. doi:10.1158/1538-7445.AM2013-5638