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

厄洛替尼是EGFR酪氨酸激酶抑制剂，是治疗非小细胞肺癌的有效药物。然而，固有的或获得性的化疗耐药是已知的抗癌治疗的主要障碍。我已经分离出厄洛替尼耐药的人类非小细胞肺癌A549细胞。PAK-104P抑制p-gp、MRP1、MRP2和主要拱顶蛋白（MVP）的功能。PAK-104P部分逆转了厄洛替尼耐药性。据报道，MVP介导对表皮生长因子受体靶向剂如厄洛替尼的耐药性。我确定了调控MVP表达的关键MVP启动子元素。通过缺失分析，一个保守的近端E-box结合位点被证明对人类MVP启动子的激活很重要。引入针对已知能结合E-box结合位点的usf1的siRNA，降低了MVP的表达。这些发现表明，USF1与E-box元件的结合可能是基础MVP启动子激活的关键。

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.