Lung cancer is the leading cause of cancer-related deaths in the developed world. In Brazil, recent data indicated that this disease caused approximately 14715 fatalities in 2000. Non-small cell lung cancer (NSCLC) accounts for 80% of all primary pulmonary tumors. For advanced NSCLC just about a third of patients survive for longer periods on conventional combination chemotherapy. Current understanding of the molecular aspects of cancer biology resulted in the development of novel drugs directed at specific targets associated with tumorigenesis, such as the inhibition of the epidermal growth factor (EGF) pathway. Gefitinib and Erlotinib for instance, are being used as an alternative therapy in the treatment of a subgroup of patients with NSCLC. In these patients, specific mutations in the EGFR gene, which render the EGFR sensitive to these compounds, have been found. Exposure to these drugs results is an inhibition of the EGF pathway and tumor growth.
One of the goals of our work is to identify mutations in the EGFR gene in primary tumors from new patients with NSCLC. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib or erlotinib. Besides, at present, the frequency of mutations in the EGFR gene in the brazilian population is unknown. This study would then provide a better insight into which drugs would be more suitable for treatment of this specific population.
So far, 25 lung cancer patients were analyzed. One showed a somatic mutation in the tyrosine kinase domain of the EGFR gene. This mutation was an in-frame deletion clustered around the ATP-binding pocket of the tyrosine kinase domain and was the same as the previously described del E746-A750 that is associated with sensitivity of NSCLCs to gefitinib.
A second goal of our work is to access the role of HDACi(Histone deacetylase inhibitor) in the tumorigenesis of NSCLC cells. The main function of HDACs is to adjust chromatin structure by controlling the level of acetylation of the histones. Inhibitors of HDAC result in growth arrest and apoptosis in some tumor cells, including some NSCLC. Cell-lines A549 and H460 are currently being tested for the effects of HDAC inhibitors on the regulation of the levels of EGFR protein and mRNA.