One important target for lung cancer therapy is the epidermal growth factor receptor (EGFR). Small molecule inhibitors of EGFR tyrosine kinase activity act by inhibiting EGFR autophosphorylation and subsequently inhibit tumor growth in a subset of advanced lung cancer patients. A key pathway downstream of EGFR is the Signal Transducers and Activators of Transcription (STAT) pathway. STATs are a family of latent cytoplasmic transcription factors that form dimers when activated by tyrosine kinase signals and translocate to the nucleus to regulate expression of genes by binding to elements within promoters. Stat3 regulates a number of pathways important in tumorigenesis including cell cycle progression, apoptosis, tumor angiogenesis, invasion and metastasis, and tumor cell evasion of the immune system. We have previously demonstrated that Stat3 acts as a survival signal in NSCLC since either direct or indirect approaches to inhibit Stat3 in NSCLC cells results in apoptosis. Using gene expression analysis, we have identified novel Stat3-regulated genes involved in the """"""""hallmarks of cancer"""""""" including genes that regulate cell growth and survival. More recently, we have found that cell lines with mutations in the tyrosine kinase domain of EGFR that are sensitive to gefitinib have high levels of activated Stat3. Correlative lab studies on early stage NSCLC show that nearly 50% of tumors possess highly correlated activated EGFR and Stat3 expression that predicts low levels of tumor apoptosis in vivo. Our results suggest that a subset of NSCLC tumors may become """"""""addicted"""""""" to EGFR-Stat3 signaling and are therefore dependent on continuous signaling from this pathway for growth and survival. Given the high level of Stat3 in NSCLC with EGFR mutations and the importance of Stat3 in oncogenesis, we hypothesize that Stat3 is an excellent molecular target in this subset of NSCLC. Direct targeting of Stat3 may have potent anti-tumor effects and may be used on combination therapy along with other agents targeting survival signaling pathways in NSCLC. Our central hypothesis is that the activating mutations of the EGFR in NSCLC leads to constitutive activation of Stat3 signaling, which in turn results in induction of a set of downstream target genes that are critical in NSCLC survival and progression.
The specific aims are: (1) to characterize the signaling events responsible for activation of Stat3 by distinct mutant EGFR proteins, (2) to characterize the role of Stat3 in regulating proliferation and survival of EGFR-dependent NSCLC, and (3) to evaluate the effects of gefitinib on EGFR-Stat3 signaling in vivo in a prospective clinical trial

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Timmer, William C
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H. Lee Moffitt Cancer Center & Research Institute
United States
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