Abstract
Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic “driver” mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations.
Highlights
Non-small cell lung carcinoma (NSCLC) is characterized by a remarkable variety of genomic alterations and point mutations that collectively disrupt the normal molecular programs which regulate growth and survival of the lung epithelium [1,2]
Immunoblot analysis of these pathways confirmed the findings of the phosphoprotein array, suggesting that STAT3 is activated independent of epidermal growth factor receptor (EGFR) in these NSCLC cells (Fig. 1C)
We observed that MEK1/2 inhibition increases STAT3 phosphorylation, suggesting that STAT3 may be activated in response to a decrease in MEK activity downstream of Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling (Fig. 2A) [25]
Summary
Non-small cell lung carcinoma (NSCLC) is characterized by a remarkable variety of genomic alterations and point mutations that collectively disrupt the normal molecular programs which regulate growth and survival of the lung epithelium [1,2]. The key ‘‘driver oncogenes’’ that have been associated with NSCLC include Kirsten rat sarcoma viral oncogene homolog (KRAS) and several receptor tyrosine kinases (RTK) such as the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), anaplastic lymphoma kinase (ALK) and hepatocyte growth factor receptor (HGFR/MET) [3]. All of these oncogenes converge upon a number of signaling pathways that have been recurrently implicated across the spectrum of solid tumors. Recent work in several different cancer types has indicated a particular role for the microenvironment— including both stromal and inflammatory cells—in acquired drug resistance, though the specific signaling mechanisms associated with this process remain incompletely understood [4,8,9]
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