SRC proteins can link receptor tyrosine kinases to critical downstream oncogenic pathways such as PI3K/PTEN/Akt, STATs, and Ras/Raf/ERK. Regulation of these key pathways allows SRC to control cellular growth and proliferation, survival, invasion, and angiogenesis. Based on the importance of EGFR signaling in lung cancer and the known cooperation between EGFR and SRC proteins, we evaluated the effectiveness of novel SRC inhibitors in lung cancer cell lines with defined EGFR status. SRC inhibition reduces mutant EGFR lung cancer cell viability through the induction of apoptosis while having no significant apoptotic effect on cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds to downregulation of activated Akt and Stat3 survival proteins. In cell lines without EGFR mutation, SRC inhibition reduces cyclin D and increases p27 protein levels with a corresponding G1 cell cycle arrest. SRC inhibition also inhibits activated FAK and inhibits lung cancer cell invasion. These data demonstrate that novel SRC inhibitors could be effective therapy for patients with lung cancers, especially those driven by mutant EGFR proteins. The goal of this research proposal is to further characterize the effect of novel SRC kinase inhibitors in lung cancer cells.
In specific aim 1, we will characterize the effect of SRC inhibitors on apoptosis and growth inhibition in lung cancer cells with defined EGFR status. We will evaluate the effects on key downstream pathways that control apoptosis and cell growth such as PI3K/PTEN/Akt and STATs. We will evaluate the effect of combined EGFR and SRC tyrosine kinase inhibitors on apoptosis and growth inhibition. Novel biomarkers will be identified through phospho-proteomics.
In specific aim 2, we will evaluate the effect of SRC inhibition on tumor growth in vivo in lung cancer xenograft models with corresponding biomarker analysis. We plan to test the hypothesis that SRC inhibitor treatment of lung cancer xenografts with EGFR mutation will undergo tumor regression through enhanced apoptosis while treatment of xenografts with wildtype EGFR will result in growth inhibition. Biomarkers of response defined in the above aim will be further validated in these models.
In specific aim 3, we will conduct an investigatorinitiated patient-based phase II trial of erlotinib &dasatinib in previously treated NSCLC along with biomolecular analysis based on mechanisms defined in Aims 1&2.
|Li, Yafang; Xiao, Xiangjun; Han, Younghun et al. (2018) Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population. Carcinogenesis 39:336-346|
|Li, Qian; Balagurunathan, Yoganand; Liu, Ying et al. (2018) Comparison Between Radiological Semantic Features and Lung-RADS in Predicting Malignancy of Screen-Detected Lung Nodules in the National Lung Screening Trial. Clin Lung Cancer 19:148-156.e3|
|Ctortecka, Claudia; Palve, Vinayak; Kuenzi, Brent M et al. (2018) Functional Proteomics and Deep Network Interrogation Reveal a Complex Mechanism of Action of Midostaurin in Lung Cancer Cells. Mol Cell Proteomics 17:2434-2447|
|Ji, Xuemei; Bossé, Yohan; Landi, Maria Teresa et al. (2018) Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nat Commun 9:3221|
|Rosenberger, Albert; Hung, Rayjean J; Christiani, David C et al. (2018) Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners. Int Arch Occup Environ Health 91:937-950|
|Dai, Juncheng; Li, Zhihua; Amos, Christopher I et al. (2018) Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci. Carcinogenesis :|
|Ferreiro-Iglesias, Aida; Lesseur, Corina; McKay, James et al. (2018) Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity. Nat Commun 9:3927|
|Li, Qian; Kim, Jongphil; Balagurunathan, Yoganand et al. (2017) Imaging features from pretreatment CT scans are associated with clinical outcomes in nonsmall-cell lung cancer patients treated with stereotactic body radiotherapy. Med Phys 44:4341-4349|
|Gimbrone, Nicholas T; Sarcar, Bhaswati; Gordian, Edna R et al. (2017) Somatic Mutations and Ancestry Markers in Hispanic Lung Cancer Patients. J Thorac Oncol 12:1851-1856|
|Lohavanichbutr, Pawadee; Sakoda, Lori C; Amos, Christopher I et al. (2017) Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium. Clin Cancer Res 23:7550-7557|
Showing the most recent 10 out of 108 publications