This is a new SPORE project that evolved from a previously-funded SPORE Pilot project. The overall goal is to develop the Fibroblast Growth Factor Receptor (FGFR) pathway as a therapeutic target in lung cancers. Tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK have greatly impacted the treatment of lung cancers driven by oncogenic forms of these receptor tyrosine kinases (RTKs). Still, a large fraction of lung cancers, especially of non-adenocarcinoma histologies, have no identified driving oncogene and remain an important and unmet clinical need. Our studies have unveiled a role for an FGFR pathway as an oncogene driver in NSCLC cell lines of diverse histologies. FGFR-dependency occurs independently of gain-of-function mutations, although FGFR1 gene amplification and/or copy number gain have recently been described in squamous lung cancers. In addition, rare somatic mutations in FGFR2 and FGFR3 have been reported in lung cancers, although their potential as oncogene drivers has not been defined. FGFR1 gene copy number is being employed as a pre-selection marker in early phase trials of the FGFR-specific TKIs, AZD4547 and BGJ398. While we will further explore FGFR1 copy number gain, our preclinical findings reveal that other predictive biomarkers (FGFR1 mRNA and protein expression) may more accurately identify FGFR-dependent, and therefore FGFR-specific TKI sensitive, lung cancers. Specifically, we have shown that FGFR activity depends on expression of FGFR1 and co-expression of the ligands, FGF2 or FGF9, thereby establishing an autocrine mechanism to drive increased FGFR activity. We will test the hypothesis that an FGF-FGFR1 autocrine pathway serves as a frequent oncogenic driver across all histologies of lung cancers and that specific biomarkers beyond FGFR1 gene copy number will serve as predictive biomarkers of lung cancer patients likely to respond to FGFR-selective TKIs. To test this hypothesis, we will complete the following specific aims.
Specific Aim 1 : Define biomarkers that accurately identify the subset of lung cancers bearing activated FGFR pathways.
Specific Aim 2 : Use optimized biomarker selection strategies to conduct a phase II clinical trial with the FGFR-active TKI, ponatinib in lung cancer patients.
Specific Aim 3 : Identify mechanisms of acquired resistance to FGFR-specific TKIs. Successful completion of this project will exert high impact on overall lung cancer treatment by unveiling a novel and substantial subset of lung tumors that are not presently identifiable through simple mutation screening nor targetable by an approved therapeutic.

Public Health Relevance

Lung cancer is a heterogeneous disease comprised of molecularly distinct subsets driven by different oncogenes. Our proposal will unveil molecular biomarkers that identify lung tumors where oncogenesis is caused by over-activity of the fibroblast growth factor receptor pathway and complete a clinical trial with ponatinib, a small molecule inhibitor of fibroblast growth factor receptors. Successful completion of the study may provide a novel targeted therapy for a significant subset of lung cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
United States
Zip Code
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