Abstract 4689: Inhibition of IL-6/Jak/Stat3 signaling: a novel and potent targeting therapy for lung cancer
Authors: Gao Sizhi P. , Mao Ninghui , Schori Erez , Liu Shuhui , Daly Laura , Barlas Afsar , Gueorguiev Volodia D. , Zhao Huiyong , Qiu Juan , Hefter Blake , Regales Lucia , Chmielecki Juliann , Pao William , Bromberg Jacqueline F. 
Published: June 2012

Non-small cell lung cancer (NSCLC) is the leading cause of death in the United States. A fraction of these tumors harbor somatic activating mutations in the epidermal growth factor receptor (EGFR) leading to constitutive activation of the kinase. Targeting this pathway using a class of tyrosine kinase inhibitors (TKI) such as gefitinib or erlotinib induces significant initial responses in patients with NSCLC expressing activating EGFR mutations, however, disease progression invariably occurs in part due to the outgrowth of cancers with EGFR TKI resistant secondary mutations. There are many ongoing attempts to overcome this problem, but the current efforts are mostly focused on EGFR itself and their effectiveness remains inconclusive. The interleukin-6 (IL-6) /Jak/Stat3 signaling pathway is critical not only for inflammation and immunity, but also for oncogenesis. Stat3 is persistently activated in many human cancers, promoting tumorigenesis through the regulation of genes important for proliferation, apoptosis, invasion, angiogenesis and suppression of anti-tumor immunity. We previously determined that Stat3 is activated in mutant EGFR expressing NSCLC cell lines and primary tumors in part through autocrine upregulation of the IL-6 gene that activates the gp130/Jak signaling. In our current report, we studied the in vivo effect of inhibiting the IL-6/Jak/Stat3 signaling in EGFR TKI-resistant models of NSCLC. Our data demonstrated that Jak inhibition by a novel orally available Jak inhibitor markedly repressed in vivo growth of 3 different TKI resistant NSCLC cell lines as well as a TKI sensitive cell line. Immunohistochemical analyses of these samples revealed reduced proliferation and angiogenesis in Jak inhibitor treated tumors. In addition, administration of an IL-6R blocking antibody to xenograft tumors of a TKI resistant NSCLC cell line also achieved significant reduction in tumor growth compared to controls. We further tested the potential role of IL-6 in a transgenic murine model of TKI-resistant, mutant EGFR mediated lung cancer. Our results demonstrated mice lacking IL-6 still developed lung tumors but at a much slower rate of tumor progression compared to IL-6 expressing littermates. Additional examinations showed that mice lacking IL-6 developed tumors with papillary features compared to IL-6 expressing littermates whereas most of the tumors were of the more advanced, solid/pleiomorphic subtype. IL-6 deficient lung tumors had decreased proliferation and angiogenesis compared to tumors from wildtype littlermates. In summary, our findings lead us to hypothesize that the IL-6/Jak pathway should be considered as a novel therapeutic target for this disease, especially TKI resistant NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4689. doi:10.1158/1538-7445.AM2011-4689