Epigenetic Mechanisms of Drug Resistance in Renal Cell Carcinoma

受体酪氨酸激酶抑制剂(RTKIs)如舒尼替尼、帕佐帕尼和阿西替尼是有效的治疗药物 适用于肾透明细胞癌(CcRCC)患者。然而，对RTKIs的抵抗是 晚期肾细胞癌的临床处理。尽管临床受益，但对RTKIs的获得性耐药仍会发生 在一线设置的12个月内。我们的初步数据表明，多梳基因的表达 组蛋白甲基转移酶Zust Homolog2或EZH2的蛋白增强子可能与舒尼替尼有关 患者来源的异种移植模型(PDX)和人肾细胞癌细胞系的耐药性。巧合的是，情况正好相反- 我们的PDX模型长期暴露于舒尼替尼的蛋白质相分析显示，显著上调了 雄激素受体(AR)在耐药后的表达。有趣的是，AR在RCC和a中表达 EZH2和AR之间的串扰已被提出用于前列腺癌。我们的初步数据还表明 舒尼替尼与EZH2或AR抑制剂联用的抗肿瘤作用强于单用 体外和体内的药物。 这项应用的总体目标是确定表观遗传学在抗性机制中的作用。 RTKis在ccRCC中的作用，以评估与这种耐药表型相关的表观基因组特征，并 开发新的治疗策略来诱导表观遗传重新编程，从而克服 对RTKI的响应。我们的中心假设是，对RTKIs的(后天和/或先天)抵抗可能是由 通过可逆的表观遗传变化和分子特征的抗性表型将导致 确定治疗干预的新靶点。综上所述，我们假设EZH2和AR 可能导致肾癌对RTKIs的肿瘤适应性和这些药物的直接抗肿瘤作用的丧失 我们将测试我们的中心假设，从而通过追求 具体目的如下：1)确定EZH2和AR在肾细胞癌模型RTKIs耐药中的作用； 2)在ccRCC模型中评估EZH2和AR调制对逆转RTKIs抗性的影响；3) 评估慢性肾细胞癌患者的EZH2和AR状态，并将其与RTKIs的反应相关联。 我们期望这些研究将提供1)改进RKTI治疗的方向；2)表观遗传学特征 与RTKIs的抗药性相关；以及3)新的预测性生物标志物和靶标的初步数据 适合于治疗性干预。总而言之，这些研究的结果将提供有用的 可以在临床环境中翻译并对晚期癌症的治疗产生影响的信息 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.