Epigenetic Mechanisms of Drug Resistance in Renal Cell Carcinoma

受体酪氨酸激酶抑制剂（RTKI），如舒尼替尼，帕唑帕尼和阿西替尼是有效的治疗方法 透明细胞肾细胞癌（ccRCC）患者。然而，对RTKI的抵抗是一个主要障碍， 晚期ccRCC的临床管理。尽管有临床益处，但对RTKI的获得性耐药性仍会发生， 在12个月内在第一线设置。我们的初步数据表明，多梳的表达， zeste同源物2或EZH2（一种组蛋白甲基转移酶）的蛋白增强子可能与舒尼替尼相关 在患者来源的异种移植模型（PDX）和人RCC细胞系中的耐药性。偶然的，一个相反的- 我们的PDX模型长期暴露于舒尼替尼的蛋白质时相分析显示， 雄激素受体（AR）表达的耐药。有趣的是，AR在RCC中表达， 在前列腺癌中已经提出了EZH2和AR之间的串扰。我们的初步数据还表明 舒尼替尼与EZH2或AR抑制剂的组合具有比单一EZH2或AR抑制剂更大的抗肿瘤作用。 在体外和体内的药剂。 本申请的总体目标是确定表观遗传学在耐药机制中的作用， 在ccRCC中使用RTKI，以评估与该耐药表型相关的表观基因组特征，并 开发新的治疗策略，以诱导表观遗传重编程，从而克服基因丢失。 对RTKI的回应我们的中心假设是，对RTKIs的（获得性和/或先天性）抗性可能是由 通过可逆的表观遗传变化和抗性表型的分子表征， 确定治疗干预的新靶点。综上所述，我们假设EZH2和AR 可能导致肿瘤对RTKI的适应，并使这些药物在RCC中的直接抗肿瘤作用丧失 我们将测试我们的中心假设，从而通过追求 以下三个具体目标：1）确定EZH2和AR在ccRCC模型中RTKI抗性中的作用; 2)评估EZH2和AR调节对逆转ccRCC模型中RTKI抗性的影响; 评估ccRCC患者中的EZH2和AR状态，并将其与对RTKI的反应相关联。 我们希望这些研究将提供1）改进RKTI治疗的方向; 2）表观遗传特征 与对RTKI的抗性相关;以及3）新的预测性生物标志物和靶标的初步数据 适合于治疗干预。总之，这些研究的结果将提供有用的 信息可以在临床环境中转化，并在治疗晚期 肾癌

Receptor tyrosine kinase inhibitors (RTKIs) such as sunitinib, pazopanib and axitinib are effective treatments for clear cell renal cell carcinoma (ccRCC) patients. However, resistance to RTKIs represents a major hurdle in the clinical management of advanced ccRCC. Despite the clinical benefit, acquired resistance to RTKIs occurs within 12 months in the first line setting. Our preliminary data suggest that the expression of the polycomb protein enhancer of zeste homolog2 or EZH2, a histone methyltransferase, may be associated with sunitinib resistance in patient-derived xenograft models (PDXs) and human RCC cell lines. Serendipitously, a reverse- protein phase analysis of our PDX model chronically exposed to sunitinib showed a significant upregulation of the androgen receptor (AR) expression following drug resistance. Interestingly, AR is expressed in RCC and a cross-talk between EZH2 and AR has been proposed in prostate cancer. Our preliminary data also suggest that the combination of sunitinib and either EZH2 or AR inhibitors has greater antitumor effect than single agents both in vitro and in vivo. The overall objective of this application is to determine the role of epigenetics in resistance mechanisms to RTKIs in ccRCC, to assess the epigenomic signature associated with this resistance phenotype, and to develop novel therapeutic strategies to induce epigenetic reprogramming and consequently overcome loss of response to RTKIs. Our central hypothesis is that (acquired and/or innate) resistance to RTKIs may be caused by reversible epigenetic changes and molecular characterization of the resistant phenotype will lead to the identification of novel targets for therapeutic interventions. Taken together, we hypothesize that EZH2 and AR may drive tumor adaption to RTKIs and loss of direct antitumor effect of these drugs in RCC We will test our central hypothesis and, thereby, accomplish the objective of this application by pursuing the following three specific aims: 1) To determine the role of EZH2 and AR in RTKIs resistance in ccRCC models; 2) To assess the impact of EZH2 and AR modulation on reversing RTKIs resistance in ccRCC models; 3) To assess EZH2 and AR status in ccRCC patients and correlate it with response to RTKIs. We expect that these studies will provide 1) a direction to improve RKTI therapy; 2) the epigenetic signature associated with resistance to RTKIs; and 3) preliminary data for novel predictive biomarkers and targets suitable for therapeutic intervention. Taken together, the results from these studies will provide useful information that can be translated in the clinical setting and have an impact in the treatment of advanced kidney cancer.