Lung cancers are the leading cause of cancer deaths globally. In particular, non-small cell lung cancer (NSCLC) is a devastating disease, and is rarely curable. While targeted therapies, such as those using epidermal growth factor receptor (EGFR) inhibitors, have shown clinical promise, these therapies are rarely curative for advanced cancers. As lung cancers are typically diagnosed at advanced phases and appear to possess inherent or acquired survival mechanisms that can protect the cells from EGFR inhibition, the discovery of pathways that mediate these compensatory survival mechanisms could reveal novel therapeutic targets that render EGFR inhibition a more effective therapy for lung cancer. Using a genome-wide shRNA screen, we have identified gene products whose inhibition synergizes with the EGFR inhibitor gefitinib to eliminate NSCLC cells. This screen identified a number of druggable gene products and potential pathways, including Wnt/tankyrase/?-catenin and NFAT/cytokine/STAT pathways. We refer to gene products whose inhibition sensitizes NSCLC cells to gefitinib treatment as 'SLuGs'for Synthetic Lethal upon Gefitinib. Follow up studies have shown that inhibition of these SLuG pathways potently synergizes with gefitinib to eliminate NSCLC cells. These studies will involve close collaborations between labs with expertise in genome-wide shRNA screens and cancer biology (DeGregori), computational biology (Tan), mouse models of NSCLC (Chan), and clinical application (Bunn). We will perform computational analysis and systematic validation of genome-wide shRNA screening results to reveal genes and pathways whose inhibition sensitizes NSCLC cells to EGFR inhibition. Further studies of the Wnt/tankyrase/?-catenin and NFAT/cytokine/STAT pathways show reveal roles for these pathways in NSCLC cell survival during EGFR inhibition. Additional studies will determine whether inhibition of these pathways cooperates with gefitinib treatment to eliminate NSCLC in vivo using mouse models. The overarching goals of this project are 1) to identify novel drug targets or unanticipated combination therapies for NSCLC, 2) to reveal pathways and processes that maintain NSCLC cell survival in the face of EGFR inhibition, and 3) to uncover therapeutic approaches to make NSCLC, either highly or moderately EGFR-inhibitor sensitive, even more sensitive to these inhibitors, leading to longer remissions and better control of the disease.

Public Health Relevance

Lung cancer is a devastating disease, and is rarely curable. While targeted therapies, such as through inhibition of the epidermal growth factor receptor (EGFR), have shown clinical promise, these therapies are rarely if ever curative for advanced cancers. Our screen has identified pathways that contribute to lung cancer cell survival during EGFR inhibition. By targeting multiple pathways, we hope to minimize the development of drug resistance and improve therapeutic outcomes. The proposed studies could provide the necessary justification for clinical trials to treat EGFR dependent lung cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157850-03
Application #
8525104
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Alley, Michael C
Project Start
2011-09-26
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$286,021
Indirect Cost
$90,971
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Scarborough, Hannah A; Helfrich, Barbara A; Casas-Selves, Matias et al. (2016) AZ1366: An inhibitor of tankyrase and the canonical Wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition. Clin Cancer Res :
Cheng, Yebin; Gao, Dexiang; Tong, Tiejun (2015) Bias and variance reduction in estimating the proportion of true-null hypotheses. Biostatistics 16:189-204
Scarborough, Hannah A; Bunn Jr, Paul A; DeGregori, James (2015) Personalized one-two punches for lung cancer. Cell Res 25:269-70
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Singleton, Katherine R; Kim, Jihye; Hinz, Trista K et al. (2013) A receptor tyrosine kinase network composed of fibroblast growth factor receptors, epidermal growth factor receptor, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, and hepatocyte growth factor receptor drives growth and survival of head and ne Mol Pharmacol 83:882-93
Alvarez-Calderon, Francesca; Gregory, Mark A; DeGregori, James (2013) Using functional genomics to overcome therapeutic resistance in hematological malignancies. Immunol Res 55:100-15

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