SRC proteins can link receptor tyrosine kinases to critical downstream oncogenic pathways such asPI3K/PTEN/Akt, STATs, and Ras/Raf/ERK. Regulation of these key pathways allows SRC to control cellulargrowth and proliferation, survival, invasion, and angiogenesis. Based on the importance of EGFR signalingin lung cancer and the known cooperation between EGFR and SRC proteins, we evaluated the effectivenessof novel SRC inhibitors in lung cancer cell lines with defined EGFR status. SRC inhibition reduces mutantEGFR lung cancer cell viability through the induction of apoptosis while having no significant apoptotic effecton cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds todownregulation of activated Akt and Stat3 survival proteins. In cell lines without EGFR mutation, SRCinhibition reduces cyclin D and increases p27 protein levels with a corresponding G1 cell cycle arrest. SRCinhibition also inhibits activated FAK and inhibits lung cancer cell invasion. These data demonstrate thatnovel SRC inhibitors could be effective therapy for patients with lung cancers, especially those driven bymutant EGFR proteins. The goal of this research proposal is to further characterize the effect of novel SRCkinase inhibitors in lung cancer cells.
In specific aim 1, we will characterize the effect of SRC inhibitors onapoptosis and growth inhibition in lung cancer cells with defined EGFR status. We will evaluate the effectson 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 growthinhibition. Novel biomarkers will be identified through phospho-proteomics.
In specific aim 2, we willevaluate the effect of SRC inhibition on tumor growth in vivo in lung cancer xenograft models withcorresponding biomarker analysis. We plan to test the hypothesis that SRC inhibitor treatment of lungcancer xenografts with EGFR mutation will undergo tumor regression through enhanced apoptosis whiletreatment of xenografts with wildtype EGFR will result in growth inhibition. Biomarkers of response definedin the above aim will be further validated in these models.
In specific aim 3, we will conduct an investigatorinitiatedpatient-based phase II trial of erlotinib &dasatinib in previously treated NSCLC along withbiomolecular analysis based on mechanisms defined in Aims 1&2.
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