NGAL-dependent Apoptosis Resistance in NSCLC
Abstracts
Initial Award Abstract |
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Lung cancer is the leading cause of cancer-related death in the United States. The overall survival rate is only 15%. Most cases of lung cancer death, close to 90% in men and 80% in women, are caused by cigarette smoking, including second hand smoking. There is an urgent need to explore new treatment agents. Targeted cancer therapy is an emerging strategy because these agents specifically attack the molecular underpinnings of a tumor, promising remarkable efficacy with minimal toxicity. The Epithelial Growth Factor Receptor (EGFR) is an important target for lung cancer therapy, because lung cancer commonly has overexpressed EGFR or over-active EGFR. Treatment with EGFR targeted inhibitors such as gefitinib (Iressa) and erlotinib (Tarceva) has led to prolonged survival of some lung cancer patients. However, many lung cancer patients only partially respond to the drugs or relapse with drug resistance within months of beginning treatment. This has led to intensive efforts to define the mechanisms of such drug resistance.
We generated a few erlotinib-resistant NSCLC cell lines as a model of erlotinib-resistant lung cancer. We found that a protein, neutrophil gelatinase associated lipocalin (NGAL, or lipocalin-2), was expressed at higher level in erlotinib resistant cells. Cells genetically manipulated to overexpress NGAL were more resistant to cell death induced by erlotinib treatment. Examination of proteins involved in cell death revealed that Bim, whose activity is prone to cell death, was decreased by NGAL. And the decreased Bim was responsible for NGAL-mediated erlotinib resistance. NGAL increased the phosphorylation of ERK1/2, which is commonly involved in enhancing cancer cell survival ability. Treating cells with erlotinib decreased ERK1/2 phosphorylation and induced Bim, however, this effect was alleviated by NGAL. Further studies showed that NGAL promoted Bim protein degradation, thus decreased Bim level. Mice inoculated with NGAL overexpressing cells were more resistance to growth inhibition induced by erlotinib treatment. Serum NGAL levels in patients who do not respond well to erlotinib treatment were higher compared to those who respond. Based on these data, we will investigate the mechanisms of NGAL-mediated cell death resistance in human lung cancer cells and delineate the NGAL signaling pathways. We will also determine whether serum or tumor NGAL levels predict response to erlotinib treatment. Our study will clarify the potentially important role of NGAL in erlotinib resistance of NSCLC and may identify NGAL as a possible biomarker of response to erlotinib in lung cancer patients. |
