Lung cancers are common and most often present with metastatic disease that cannot be cured by systemic therapies. Recent non-small cell lung cancer (NSCLC) trials of tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) demonstrated partial responses in the majority of patients with activating EGFR mutations, but complete responses are rare and median progression-free survival remained below a year. In NSCLC patients without EGFR mutations, EGFR TKIs produce objective responses in less than 10% of patients, but with a small, statistically significant prolongation of survival. The development of drug resistance and progressive disease is universal. Improved therapy is clearly needed in both groups. Advanced lung cancers possess inherent or acquired survival mechanisms that can protect the cells from EGFR inhibition. Thus, the discovery of pathways that mediate these compensatory survival mechanisms could reveal novel therapeutic targets that would render kinase inhibition a more effective therapy for lung cancer. In the last grant period, we used a genome-wide shRNA screen and gene expression profiling to identify genes that when inhibited sensitize EGFR mutant and EGFR wild-type NSCLC cells to EGFR inhibition. These studies identified the FGFR and Wnt/?-catenin pathways as mechanisms of resistance to EGFR TKIs. We further showed that genetic and pharmacological inhibition of the FGFR pathway and multiple components of the canonical Wnt/?-catenin pathway identified in this screen, including tankyrase and casein kinase 2 (CK2), potentiated EGFR inhibitor therapy in vitro and in vivo. In this project, we propose to identify, validate and characterize signaling mechanisms underlying the inability of EGFR TKI to elicit complete therapeutic responses, in order to develop novel therapeutic combinations that can improve outcomes for patients with NSCLC. Importantly, we have been successful in the past in translating discoveries into biomarker-driven clinical trials. We will achieve these goals through three aims: 1) Pre-clinically and clinically evaluate the roles for FGFRs in innate resistance to EGFR TKI including the development of biomarkers and conduct of a Phase 1/1b clinical trials, 2) Determine optimal biomarkers for and the clinical efficacy in a Phase I/Ib clinical trial of combining EGFR TKI with tankyrase inhibitors for treatment of NSCLC, and 3) Determine biomarkers and establish the pre-clinical efficacy of combining EGFR TKI with CK2 inhibitors for treatment of NSCLC. By targeting multiple pathways, the ultimate goal of these studies is the development of therapeutic strategies for NSCLC patients that minimize the development of drug resistance and improve therapeutic outcomes.

Public Health Relevance

The majority of patients diagnosed with lung cancer have advanced stage disease at diagnosis and many others relapse after surgery and chemo-radiotherapy. Therapy in this setting is palliative and complete responses are rare. About 15% of these patients have adenocarcinomas with EGFR mutations. While EGFR TKIs are the therapy of choice, all patients progress at a median of 9-10 months. We aim to improve the outcome in these patients with scientifically driven combinations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA058187-19A1
Application #
8664637
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
19
Fiscal Year
2014
Total Cost
$274,905
Indirect Cost
$98,618
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Symonds, Jennifer M; Ohm, Angela M; Tan, Aik-Choon et al. (2016) PKCδ regulates integrin αVβ3 expression and transformed growth of K-ras dependent lung cancer cells. Oncotarget 7:17905-19
Dziadziuszko, Rafal; Le, Anh T; Wrona, Anna et al. (2016) An Activating KIT Mutation Induces Crizotinib Resistance in ROS1-Positive Lung Cancer. J Thorac Oncol 11:1273-81
Saichaemchan, S; Ariyawutyakorn, W; Varella-Garcia, M (2016) Fibroblast Growth Factor Receptors: From the Oncogenic Pathway to Targeted Therapy. Curr Mol Med 16:40-62
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 :
Poczobutt, Joanna M; Nguyen, Teresa T; Hanson, Dwight et al. (2016) Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment. J Immunol 196:891-901
Li, Bob T; Ross, Dara S; Aisner, Dara L et al. (2016) HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers. J Thorac Oncol 11:414-9
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
Ariyawutyakorn, Witthawat; Saichaemchan, Siriwimon; Varella-Garcia, Marileila (2016) Understanding and Targeting MET Signaling in Solid Tumors - Are We There Yet? J Cancer 7:633-49
Bunn Jr, Paul A; Minna, John D; Augustyn, Alexander et al. (2016) Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes? J Thorac Oncol 11:453-74
Helfrich, Barbara A; Kim, Jihye; Gao, Dexiang et al. (2016) Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo. Mol Cancer Ther 15:2314-2322

Showing the most recent 10 out of 350 publications