Research Projects

Lung cancer is the most common cancer globally, causing 1.38 million deaths per year. Non-Small Cell Lung Cancers (NSCLC) are the most common type of lung cancer, and the Epidermal Growth Factor receptor (EGFR) pathway plays a significant role in NSCLC carcinogenesis. Tyrosine Kinase Inhibitors (TKIs) like Erlotinib, Gefitinib, Afatinib, Osimertinib, and Dacomitinib are approved as the first line treatment for NSCLC. Gefitinib and erlotinib are orally bioavailable TKIs that selectively and reversibly bind to the intracellular ATP-binding site of the EGFR tyrosine kinase. Diurnal variation in hormones, diseases, and drug pharmacokinetics and pharmacodynamics has been shown to affect tumor growth in mice and humans. The metabolism and transport of TKIs influence the therapeutic response in NSCLC patients. Erlotinib is metabolized primarily by CYP3A4 and CYP1A1, while gefitinib is primarily by CYP3A4 and marginally by CYP3A5 and CYP2D6. Circadian expression of these genes underlies the chronopharmacokinetics, contributing to circadian time-dependent drug efficacy. The effect of morning vs. evening doses of TKIs and BMAL1 on blood concentration and CYP3A4 expression has not been studied yet. The role of chronopharmacokinetics and chronogenomics of TKIs may play an important role in clinical outcome in NSCLC patients considering the gene expression of CYP3A4 and BMAL1.