缺氧状态下胰腺癌细胞对特异性酪氨酸激酶抑制剂的获得性耐药的新型机理

本课题的目的是阐明胰腺癌细胞在缺氧环境下获得特异性耐药的分子机理。我们新近发现缺氧条件下多种癌细胞通过调节DEC-2从而调控MET/RON 基因的表达，获得对特异性酪氨酸激酶抑制剂的耐药性。我们的科学假设：癌细胞在缺氧下导致的获得性耐药是通过HIF-1α 调控DEC-2 转录抑制因子活性而实现。DEC-2 特异性抑制MET/RON 基因启动子转录导致TKI药物靶分子消失，癌细胞耐药性形成。围绕科学假设，项目将重点研究（1）HIF-1α 直接调节DEC-2 在缺氧性癌细胞中表达和转录抑制活性的分子机理；（2）DEC-2 在缺氧条件下是如何与MET/RON 基因的启动子结合，从而抑制MET/RON 基因的转录活性；（3）验证DEC-2 作为药靶的作用，以期逆转缺氧癌细胞对MET/RON 特异性抑制剂的耐药性，从而增强肿瘤对药物的敏感性。研究结果将为临床靶向性抗癌治疗开创新的策略。

This grant application concerns a novel discovery by which pancreatic cancer cells acquire resistance under hypoxia towards specific tyrosine kinase inhibitors (TKIs). Under hypoxia, colon and breast cancer cells acquire resistance towards MET/RON dual specific TKIs including BMS-777607 (currently under clinical trial). We hypothesize that acquired resistance to MET/RON specific TKI is caused by HIF-1α-induced DEC-2 transcription repressive activity that specifically represses MET and RON gene transcription, leading to “loss of the target”. DEC-2 regulates cell differentiation and circadian rhythms. Unexpected, we observed that DEC-2 is hypoxia-induced transcription repressors, which specifically inhibits the MET/RON gene expression and causes acquired TKI resistance. To dissect this mechanism, Specific Aim 1 will determine molecular mechanisms by which HIF-1α directly regulates DEC-2 expression and transcriptionally repressive activity in hypoxic cancer cells. Specific Aim 2 will determine how DEC-2 interacts under hypoxia with E-box sequences in the MET and RON promoters and represses their gene transcription. Specific Aim 3 will validate DEC-2 as a drug target to overcome hypoxia-induced resistance leading to increased TKI sensitivity with tumor growth inhibition in animal models. These studies will facilitate the development of a novel strategy for potential clinical application in TKI targeted cancer therapy.