Insulin-like growth factor I receptor (IGF-1R)-mediated signaling plays an important role in the proliferation, survival, and metastasis of cancer cells. The IGF-1R-targeting anticancer agents including monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) have been developed, but their antitumor effects have been marginal and limited in clinical trials. Therefore, the mechanism underlying resistance to the IGF-1R-targeting therapies and the rational combination strategies to overcome potential drug resistance need to be investigated. In this study, we demonstrated the association of Src with the resistance to the IGF-1R TKI in non-small cell lung cancer (NSCLC). We found the co-activation of IGF-1R/IR and Src in various human NSCLC cell lines, The mRNA expression and phosphorylation of IGF-1R and Src were also significantly correlated with each other in NSCLC databases from a public dataset and a tissue microarray (n=353). Next, we found Src can be activated through multiple pathways including EGFR and integrin β3 signaling and function as an alternative kinase for phosphorylation of IGF-1R, especially at Tyr1135/36, but not Tyr1131. Src is activated in lung cancer cells possessing both primary and acquired resistance to an IGF-1R TKI. Consistent with the results, inhibition of Src significantly attenuated activation of IGF-1R/IR and co-targeting of IGF-1R and Src effectively suppressed cell proliferation, colony formation, and tumor growth in vitro and in vivo. Taken together, these results suggest that Src causes resistance to IGF-1R TKIs by functioning as a key downstream modulator of multiple signaling pathways for IGF-1R phosphorylation and thus co-targeting IGF-1R and Src could be an effective therapeutic strategy for NSCLC.
Citation Format: Hye-Young Min, Hye Jeong Yun, Hyo-Jong Lee, Jaebeom Cho, Hyun-Ji Jang, Kyung Min Kim, Woo-Young Kim, Seung-Hyun Oh, Diane Liu, J. Jack Lee, Waun Ki Hong, Ignacio I. Wistuba, Ho-Young Lee. Targeting the insulin-like growth factor receptor/Insulin receptor and Src signaling network for the treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1716. doi:10.1158/1538-7445.AM2014-1716