The roles of Cyclooxygenase-2 and protein Kinase C delta in mutant epidemal growth factor receptor non-small cell lung cancer

Lung cancer causes more than 1 million deaths in every year worldwide, and is the leading cause of cancer-related death in the United States. Targeting epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) harboring activating mutations in EGFR is an effective treatment but is eventually limited by drug-resistance. This has led to a pressing need to identify alternative treatments or additional targets for resistant tumors. I found abundant activation of cyclooxygenase-2 (COX-2) signal in mutant EGFR NSCLC, suggesting that it might play tumorigenic roles in these tumors. Targeting COX-2 in mutant EGFR lung cancer cells and transgenic mouse models of mutant EGFR lung cancer reduced tumor cell growth, and was more effective in combination with EGFR inhibition. I found that COX-2 signaling regulates interleukin-6 (IL-6) transcription leading to signal transducer and activator of transcription 3 (STAT3) activation. These findings demonstrate that COX-2 modulates the IL-6/STAT3 signaling axis in mutant EGFR NSCLC and targeting COX-2 in combination with EGFR inhibition could be an effective strategy to treat mutant EGFR NSCLC. Since COX-2 inhibition is a promising chemopreventive agent in other cancers; therefore, I next hypothesized that targeting COX-2 might be a viable strategy to prevent tumor formation. Using transgenic mouse models, I found that targeting COX-2 prior to tumor development delayed tumor formation, which suggests that COX-2 inhibition could be a potential strategy to delay or prevent development of mutant EGFR NSCLC. iv In further efforts to identify other targets in mutant EGFR lung cancer, I found evidence of abundant activation of protein kinase C δ (PKCδ). This kinase normally functions as a tumor-suppressor, but it also is considered as a tumor-promoter in some contexts. I found reduced growth of mutant EGFR human lung cancer cells under PKCδ depletion. I also discovered that PKCδ promotes IL-6/STAT3 signal in mutant EGFR NSCLC, suggesting that PKCδ is a tumor-promoter in mutant EGFR NSCLC. Collectively, my data indicate that PKCδ is a potential target to treat mutant EGFR NSCLC. In this dissertation, I identified COX-2 and PKCδ as novel targets for treating mutant EGFR NSCLC and defined their oncogenic roles in mutant EGFR NSCLC by regulating the critical oncogenic signal, IL-6/STAT3.