Role of Axl in docetaxel resistance in prostate cancer

描述（由申请人提供）：虽然在前列腺癌（PCa）的早期管理方面取得了重大进展，但转移性难治性PCa几乎没有有效的治疗策略。多西他赛是用于侵袭性前列腺癌治疗的主要化疗药物，其对转移性PCa的疗效有限，主要是由于耐药性的恒定发展，因此需要彻底研究这种耐药性的机制，并开发新的更有效的治疗方法来预防或克服耐药性。受体酪氨酸激酶Axl与许多癌症的病理学有关，包括晚期PCa。此外，Axl的上调与几种癌症类型中的不良预后和对治疗的抗性有关。我们现在提供的初步证据表明，Axl是PCa对多西他赛耐药的关键驱动因素。虽然Axl的敲低以及通过药理学Axl抑制剂的Axl阻断使PCa细胞对多西他赛敏感，但是Axl过表达降低了多西他赛在PCa细胞中的功效。此外，我们证明多西他赛耐药PCa细胞的产生导致Axl表达上调，证实了我们的观点，即Axl在多西他赛耐药中发挥着关键作用。因此，我们将检验Axl激活导致多西他赛耐药的假设 在PCa中的治疗和Axl的抑制将克服、延迟或防止PCa中对多西他赛的耐药性。为了解释Axl在多西他赛耐药性中的确切作用并开发晚期PCa的新治疗策略，因此，我们将定义Axl在多西他赛和卡巴他赛耐药性PCa细胞中的表达/活性的相关性，并进行Axl抑制的临床前评估，以预防、延迟或克服雄激素受体阳性、雄激素应答和去势耐药性PCa异种移植物中的多西他赛耐药性。对Axl信号通路在多西他赛耐药中的详细机制分析将确定Axl介导的NF-κB和MAP激酶信号通路的激活是否是诱导多西他赛应答逃逸的关键。在具体目标1中，我们将评估多西他赛治疗对缺乏Axl表达的多西他赛耐药PCa细胞系的增殖、迁移、侵袭和凋亡的影响。此外，我们将评估细胞与Axl抑制剂和多西他赛的共处理以及Axl抑制剂的预处理，以确定Axl抑制剂的使用是否使细胞对多西他赛敏感。在Specific Aim 2中，对多西他赛耐药PCa异种移植物的临床前体内评估将确定Axl的敲低或药理学靶向Axl抑制是否能够预防、延迟或克服多西他赛耐药并增强多西他赛的抗肿瘤功效。具体目标3将破译精确的分子机制和信号通路参与Axl的耐药性的调节，与NF-κB和MAPK级联和雄激素信号的初始重点。Axl作为PCa中多西他赛和卡巴他赛耐药性的驱动因素的拟议研究预计将导致一种创新的联合治疗方法，用于更有效地治疗转移性PCa。

DESCRIPTION (provided by applicant): While there has been significant progress in management of early stages of prostate cancer (PCa), metastatic hormone-refractory PCa has few effective therapeutic strategies available. Docetaxel, the main chemotherapeutic drug used in aggressive prostate cancer treatment, has shown limited efficacy against metastatic PCa, primarily due to invariable development of drug resistance, necessitating a thorough investigation of the mechanisms underlying this drug resistance and the development of novel, more efficacious therapies to prevent or overcome resistance. The receptor tyrosine kinase Axl has been implicated in the pathology of many cancers, including advanced PCa. In addition, upregulation of Axl has been linked to poor prognosis and resistance to therapy in several cancer types. We are now providing preliminary evidence that Axl is the key driver of resistance to docetaxel in PCa. While knockdown of Axl as well as Axl blockage by a pharmacologic Axl inhibitor sensitizes PCa cells to docetaxel, Axl overexpression reduces docetaxel efficacy in PCa cells. Moreover, we demonstrate that generation of docetaxel-resistant PCa cells results in upregulation of Axl expression, corroborating our notion that Axl plays a critical role in docetaxe resistance. We will, thus, test our hypothesis that Axl activation leads to resistance to docetaxel therapy in PCa and that inhibition of Axl will overcome, delay or prevent resistance to docetaxel in PCa. In order to decipher the precise role of Axl in docetaxel resistance and to develop a novel therapeutic strategy for advanced PCa we will, therefore, define the relevance of Axl expression/activity in docetaxel and cabazitaxel resistant PCa cells and perform a preclinical assessment of Axl inhibition to prevent, delay or overcome docetaxel resistance in androgen receptor-positive, androgen responsive and castration-resistant PCa xenografts. Detailed mechanistic analysis of Axl signaling in docetaxel-resistance will determine whether Axl-mediated activation of NF-κB and MAP kinase signaling pathways is critical for inducing escape from docetaxel response. In Specific Aim 1 we will evaluate the effects of docetaxel treatment on proliferation, migration, invasion, and apoptosis of docetaxel resistant PCa cell lines lacking Axl expression. Furthermore, we will evaluate co-treatment of cells with the Axl inhibitors and docetaxel as well as pre-treatment with Axl inhibitors in order to determine if the use of Axl inhibitors sensitizes cells to docetaxel. In Specific Aim 2 preclinical in vivo assessment of docetaxel-resistant PCa xenografts will determine whether knockdown of Axl or pharmacological, targeted Axl inhibition is able to prevent, delay or overcome docetaxel resistance and enhances anti-tumor efficacy of docetaxel. Specific Aim 3 will decipher the precise molecular mechanisms and signaling pathways involved in Axl regulation of drug resistance, with an initial focus on the NF-κB and MAPK cascades and androgen signaling. The proposed study of Axl as a driver of docetaxel and cabazitaxel resistance in PCa is anticipated to lead to an innovative combination therapy approach for a more effective treatment of metastatic PCa.