Sizhi Paul Gao Ph.D.

This grant is being fully funded by Elliot’s Legacy, through the Uniting Against Lung Cancer Grant Program.

Lay Description

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 models injected with human cancer cells and in preclinical 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 preclinical 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.

Scientific Abstract

Recently, a novel class of somatic activating mutations in the epidermal growth factor receptor (EGFR) were identified in ~10-20% of patients with non-small-cell lung cancer (NSCLC), especially in non-smokers. Most (90%) of these somatic mutations are encoded within the tyrosine kinase domain of the EGFR and occur as either a deletion of four amino acids (del 746-750) or a missense mutation (L858R). Patients with tumors harboring either of these mutant forms of EGFR are extremely sensitive to the selective EGFR kinase inhibitors gefitinib or erlotinib but eventually develop acquired resistance and succumb to their disease. In about half the cases of acquired resistance to the EGFR kinase inhibitors, the mechanism is due to a second-site mutation in the EGFR kinase domain involving an amino acid substitution (T790M). Signal transducer and activator of transcription 3 (Stat3), is persistently tyrosine phosphorylated or activated in a large number of malignancies and plays a critical role in tumorigenesis by enhancing cell proliferation, survival, angiogenesis, inflammation and chemotherapy resistance. We discovered that Stat3 is persistently activated in 50% of NSCLC, which positively correlated with adenocarcinomas harboring somatic activating mutations in the EGFR. Importantly, we identified interleukin-6 (IL-6), a tumor promoting cytokine, as the key factor leading to persistent Janus kinase (Jak)/Stat3 activation in lung cancers. We further demonstrated that inhibition of the IL-6/Jak2/Stat3 pathway blocks the in vitro growth of NSCLC cells including those that are resistant to EGFR kinase inhibitors. We recently determined that a novel orally available Jak2 inhibitor (INCB16562) could inhibit Stat3 activation in NSCLC-derived cell lines as well as inhibit their growth in vitro. These findings suggest that IL-6/Jak2 blockade may prove to be effective therapy in the treatment of lung cancers dependent upon somatic activating mutations in the EGFR as well as those that have acquired resistance to EGFR kinase inhibitors. An inducible preclinical model of lung cancer was recently described: the bi-transgenic mouse C/ EGFRL858R+T790M, expressing the transgene CCSP-rtTA (for doxycycline inducible expression of the tet transcriptional activator within type II pneumocytes) and the tet-operator driven EGFRL858R+T790M transgene develop tumors which are resistant to EGFR kinase inhibitors. In this proposal, we will determine whether this orally available Jak2 inhibitor (INCB16562) blocks the in vivo growth of human lung cancer derived cell lines including those harboring the resistant T790M mutation. In addition, we will determine whether INCB16562 induces regression of tumor growth in the C/ EGFRL858R+T790M preclinical model of EGFR kinase inhibitor resistant lung adenocarcinoma. Furthermore, we will determine whether a deficiency of IL-6 will delay tumor development in the C/ EGFRL858R+T790M preclinical lung cancer model. 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.