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

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121182-05
Application #
8020912
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Timmer, William C
Project Start
2007-03-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$307,781
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Yoshida, Takeshi; Song, Lanxi; Bai, Yun et al. (2016) ZEB1 Mediates Acquired Resistance to the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. PLoS One 11:e0147344
Song, Lanxi; Smith, Matthew A; Doshi, Parul et al. (2014) Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer. J Thorac Oncol 9:974-82
Haura, Eric B (2012) From modules to medicine: How modular domains and their associated networks can enable personalized medicine. FEBS Lett 586:2580-5
Alexandrow, Mark G; Song, Lanxi J; Altiok, Soner et al. (2012) Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Prev 21:407-12
Zhang, Guolin; Fang, Bin; Liu, Richard Z et al. (2011) Mass spectrometry mapping of epidermal growth factor receptor phosphorylation related to oncogenic mutations and tyrosine kinase inhibitor sensitivity. J Proteome Res 10:305-19
Song, Lanxi; Rawal, Bhupendra; Nemeth, Jeffrey A et al. (2011) JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol Cancer Ther 10:481-94
Haura, Eric B; Sommers, Eric; Song, Lanxi et al. (2010) A pilot study of preoperative gefitinib for early-stage lung cancer to assess intratumor drug concentration and pathways mediating primary resistance. J Thorac Oncol 5:1806-14
Gao, Jingchun; Zheng, Zhong; Rawal, Bhupendra et al. (2009) Mirk/Dyrk1B, a novel therapeutic target, mediates cell survival in non-small cell lung cancer cells. Cancer Biol Ther 8:1671-9
Gao, Jingchun; McConnell, Matthew J; Yu, Bin et al. (2009) MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion. Int J Oncol 35:337-45