| Approximately 10% of lung cancers occur in never-smokers and typically harbor a mutant form of the epidermal growth factor receptor (EGFR). Although most of these patients initially respond to targeted inhibitors of the EGFR enzyme, they eventually develop resistance to the EGFR kinase inhibitors (and succumb to their disease) which in about 50% of cases is due to a second mutation within the EGFR. We recently determined that the signal transducer and activator of transcription 3 (Stat3) protein is aberrantly activated in both the EGFR kinase inhibitor sensitive and resistant lung cancers harboring mutant forms of the EGFR as a consequence of enhanced production of the tumor promoting factor interluekin-6. The Stat3 molecule has been shown to play a critical role in promoting a number of cancers by increasing the growth and blood supply to tumors, as well as promoting resistance to chemotherapy. Importantly, we have recently characterized a novel inhibitor of the IL-6/Stat3 pathway, which effectively blocks Stat3 activity and the growth of cultured lung cancer cells, including those that are resistant to EGFR kinase inhibitors. In this proposal, we will determine whether this inhibitor (Jak inhibitor) will block the growth of lung cancers in mice injected with human cancer cells and in mouse models of lung cancer expressing the mutant forms of the EGFR (including those that are resistant to EGFR kinase inhibitors). In addition, we will test whether removal of IL-6 by genetic deletion can decrease or delay cancer development in mouse lung cancer models. The overall aim of this proposal is to develop the necessary pre-clinical evidence of targeting the IL-6/Jak/Stat3 pathway in lung cancers including those who have developed resistance to EGFR kinase inhibitors and chemotherapy. We believe that blocking this pathway is a potentially important and novel approach to treating patients with lung cancer.
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