Molecular basis for resistance to erlotinib and development of agents that reverse the resistance

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Erlotinib, EGFR tyrosine kinase inhibitor, is an effective therapeutic agent for non-small cell lung cancer. However, inherent or acquired chemoresistance is known to be a major obstacle for anti-cancer therapies. I have isolated erlotinib resistant human non-small cell lung cancer A549 cells. PAK-104P inhibits the functions of p-gp, MRP1, MRP2 and Major vault protein (MVP). PAK-104P partially reversed the erlotinib resistance. It has been reported that the MVP mediates resistance to epidermal growth factor receptor-targeting agent such as erlotinib. I identified the crucial MVP promoter elements that regulate MVP expression. By deletion analysis, a conserved proximal E-box binding site was demonstrated to be important for human MVP promoter transactivation. Introduction of siRNA against USF 1 , which is known to bind the E-box binding site, decreased the expression of MVP. These findings suggest that USF1 binding to an E-box element may be critical for basal MVP promoter activation.