HMGA2 mediates resistance to therapy in prostate cancer

项目总结 上皮间充质转化(EMT)在上皮性癌症中有很好的特征，其中肿瘤细胞位于 侵袭性前锋失去E-钙粘蛋白等上皮标志物，获得波形蛋白等间充质标志物， 促进侵袭、迁移和随后的转移；它可以由转录因子促进，如 高移动组A2(HMGA2)。转移性前列腺癌的治疗是有问题的，特别是当它成为 转移和抗去势(MCRPC)。目前治疗转移性前列腺癌的一线激素疗法包括 抑制雄激素生物合成的阿比特龙和与雄激素受体(AR)和 阻止其移位到细胞核，而在欠发达国家，这些新的荷尔蒙 目前尚无治疗方法，多西紫杉醇是主要治疗方法。然而，对这些药物的耐药性通常 发展和EMT已被证明是造成这种耐药性的原因。神经内分泌晚期PCA一直以来 用Aurora A激酶抑制剂Alisertib/MLN8237治疗，而MLN8237与 9例mCRPC中的阿比特龙因毒性和缺乏临床益处而停用。有趣的是， MLN8237抑制胰腺癌细胞和卵巢癌细胞的EMT。HMGA2在胰腺、肺组织中的过表达 癌症和口腔癌，前列腺癌是在促进EMT的地方发表的，而我们 报道了全长但不截断(缺失3‘非编码区)的HMGA2促进EMT。我们的初步数据来自 在444例转移性前列腺癌患者中，有3%的患者HMGA2基因扩增。43%的 这些HMGA2扩增的转移患者接受阿比特龙治疗，而21%的患者接受 苯扎鲁胺和36%的人接受了MLN8237。有趣的是，我们进一步证明MLN8237能够抑制细胞 高表达全长/野生型和截短型HMGA2及LNCaP Neo的LNCaP细胞的生长 控制单元。然而，只有野生型HMGA2对多西紫杉醇和苯扎鲁胺具有抵抗力 与表达截断的细胞相比，AR在细胞核内的表达和定位增加 HMGA2。假设是野生型HMGA2使人对多西紫杉醇和激素治疗产生抵抗。 在转移性前列腺癌中，通过AR依赖和独立的机制，可以通过 用MLN8237处理，或先用MLN8237预处理以抑制EMT，然后再用 激素疗法。我们将确认对多西紫杉醇、苯扎鲁胺和阿比特龙的耐药性。 依赖和AR非依赖性细胞株通过调控HMGA2的表达和 分析HMGA2在耐药细胞中的表达和定位，并阐明其作用机制。 我们还将研究MLN8237是否抑制PCa中的EMT，以及单独和联合使用的效果 活体内的治疗。我们的研究将有力地表明野生型HMGA2可以作为生物标记物 避免使用激素治疗，而使用MLN8237或使用MLN8237进行预治疗以抑制 EMT后用多西紫杉醇或苯扎鲁胺治疗。

PROJECT SUMMARY Epithelial-mesenchymal transition (EMT) is well characterized in epithelial cancers where tumor cells at the invasive front lose epithelial markers such as E-cadherin, gain mesenchymal markers such as vimentin, to promote invasion, migration and subsequent metastasis; it can be promoted by transcription factors such as High Mobility Group A2 (HMGA2). Treatment for metastatic PCa is problematic, especially if it becomes metastatic and castration-resistant (mCRPC). Current first-line hormone therapy for metastatic PCa includes abiraterone that inhibits androgen biosynthesis, and enzalutamide that binds to androgen receptor (AR) and prevents its translocation to the nucleus, while in less developed nations where these novel hormonal therapies are not available, docetaxel is the main therapy. However, resistance to these drugs usually develops and EMT has been shown to contribute to this resistance. Neuroendocrine advanced PCa has been treated with Aurora A kinase inhibitor, alisertib/MLN8237, while combination treatment of MLN8237 with abiraterone in mCRPC in 9 patients was terminated due to toxicity and lack of clinical benefit. Interestingly, MLN8237 inhibits EMT in pancreatic and ovarian cancer cells. Overexpression of HMGA2 in pancreatic, lung carcinomas and carcinoma of oral cavity, and prostate cancer is published where it promotes EMT, while we reported that full-length but not truncated (missing 3’UTR) HMGA2 promotes EMT. Our preliminary data from cBioportal in 444 metastatic PCa patients shows that 3% of the patients show HMGA2 amplification. 43% of these metastasis patients with HMGA2 amplification received abiraterone treatment, while 21% received enzalutamide and 36% received MLN8237. Interestingly, we further show that MLN8237 is able to inhibit cell growth in LNCaP cells overexpressing both full-length/wild-type and truncated HMGA2 as well as LNCaP Neo control cells. However, only wild-type HMGA2 confers resistance to docetaxel and enzalutamide concomitant with increased AR expression and localization within the nucleus, compared to cells expressing truncated HMGA2. The hypothesis is that wild-type HMGA2 confers resistance to docetaxel and hormone therapy in metastatic PCa via AR-dependent and -independent mechanisms that may be overcome by treatment with MLN8237, or pre-treatment with MLN8237 to first inhibit EMT followed by treatment with hormone therapy. We will confirm resistance to docetaxel, enzalutamide and abiraterone in several AR- dependent and AR-independent cell lines expressing HMGA2 by manipulating HMGA2 expression and analyzing HMGA2 expression and localization in cells resistant to these drugs and elucidate the mechanisms. We will also examine whether MLN8237 inhibits EMT in PCa and the effect of single and combination treatments in vivo. Our studies will be impactful in showing that wild-type HMGA2 can be used as a biomarker to avoid treatment with hormonal therapy and instead utilize MLN8237 or pre-treat with MLN8237 to inhibit EMT followed by treatment with docetaxel or enzalutamide.