Abstract 168: Cytokine signaling through the JAK2/STAT3 pathway is a viable therapeutic target in non-small cell lung cancer

Abstract

Abstract The emergence of molecular methods for classifying solid tumors based upon specific “driver mutations” has made rationally-designed chemotherapy possible in a variety of cancers. Non-small cell lung carcinoma (NSCLC) is a prototypical example of these clinical advances, and is routinely treated with targeted kinase inhibitors including erlotinib and gefitinib. Despite the success of this approach, drug resistance continues to be a significant problem in patients with advanced NSCLC. Constitutive activation of STAT3 is a common feature in non-small cell lung carcinoma (NSCLC), and has been proposed to play an important role in tumor cell resistance to conventional and targeted small-molecule therapies. Previous studies have suggested that STAT3 can be activated in NSCLC by hyperactive growth factor receptors or cytokine signaling, though the interplay between STAT3 activation and other well-characterized oncogenic “driver” mutations in NSCLC has not been fully characterized. We analyzed the activation status of key growth factor signaling pathways in seven NSCLC lines with four distinct classes of driver mutations, including activating mutations to KRAS and several receptor tyrosine kinases (EGFR, MET, PDGFRA). Targeted pharmacologic inhibitors were used to evaluate the relative contribution of each oncogene to signaling pathway activation. While common downstream effectors such as ERK, AKT, mTOR were repressed by these drugs, we observed that STAT3 remained activated in all seven cell lines independent of mutational subtype. However, pharmacologic or genetic inhibition of the gp130/Janus kinase (JAK2) signaling pathway uniformly disrupted STAT3 activation. Interestingly, only 3/7 lines produced significant levels of the cytokine interleukin-6 (IL-6), which was previously suggested to be the key mediator of gp130/JAK2 signaling in NSCLC. Gene expression and ELISA analysis of other IL-6 family ligands suggests that cardiotrophin-like cytokine factor-1 (CLCF1) may be responsible for pathway activation in the other four cell lines lacking IL-6. At the functional level, treatment of cells with the JAK1/2 inhibitor ruxolitinib had little effect on proliferation and viability in two-dimensional culture, though it inhibited anchorage-independent growth of NSCLC cells in soft agar. Ruxolitinib also slowed growth of xenografted NSCLC cells, indicating that JAK2 activity is required for optimal growth of lung tumors in vivo. Together these results demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and may play a key role in growth and/or progression of lung tumors. We suggest that addition of a JAK2 inhibitor to therapies which target commonly altered oncogenes such as KRAS or EGFR will improve clinical outcomes for NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 168. doi:1538-7445.AM2012-168