Abstract 1814: IL11 mediates tumor resistance to anti-VEGF therapy in lung cancer

Abstract

Anti-angiogenic therapy has been used for the treatment of a number of solid tumors in clinic, however, survival benefit is often limited due to development of tumor resistance to the therapy. In previous studies, we developed a mouse Lewis lung carcinoma (LLC) tumor model that is resistant to anti-VEGF therapy. In this model, we identified that Interleukin 11 (IL11) was among the most significantly upregulated genes in the resistant tumors. In current study, we demonstrated that IL11 was a pro-angiogenic factor and played a key role in the development of resistance to anti-VEGF therapy in LLC tumor. IL11 could effectively induce HUVEC proliferation, migration and capillary tube formation in vitro. It enhanced expression of MMP9 in endothelial cells. The conditioned medium from the resistant LLC cell culture could induce HUVEC migration, even VEGF was blocked, and this effect was attenuated by recombinant IL11 decoy receptor, an IL-11 inhibitor. Furthermore, combination therapy of anti-VEGF agent and IL11 blockade exhibited enhanced anti-tumor activity in lung cancer model. In addition, based on bioinformatics analysis on over 500 RNA-seq data deposited to The Cancer Genome Atlas (TCGA), we found that IL11 was highly expressed in various tumor types in patients. Data showed that high IL11 can predict a poor outcome in the lung cancer. The patients with the lower IL11 expression have significantly longer median survival time than those with higher expression. These findings support a role of IL11 signal as a compensatory angiogenic pathway that might trigger tumor resistance to anti-VEGF treatment. Therapeutically targeting IL11 could have a value in overcoming tumor resistance to anti-VEGF therapy. Citation Format: Jie Li, Kun Xie, Shenglin Mei, Yuanjian Xu, Hua Gu, Dong Li, Kaiming Chen, Fei Tao, Jiya Eerdeng, Jianmin Fang. IL11 mediates tumor resistance to anti-VEGF therapy in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1814. doi:10.1158/1538-7445.AM2017-1814