Role of Axl in docetaxel resistance in prostate cancer

描述(由申请人提供)：虽然前列腺癌(PCA)的早期治疗已经取得了重大进展，但转移性激素耐药的前列腺癌几乎没有有效的治疗策略可用。多西紫杉醇是用于侵袭性前列腺癌治疗的主要化疗药物，其对转移性前列腺癌的疗效有限，主要是由于耐药的持续发展，需要深入研究这种耐药的机制，并开发新的、更有效的治疗方法来预防或克服耐药。受体酪氨酸激酶Axl参与了许多癌症的病理过程，包括晚期前列腺癌。此外，在几种癌症类型中，Axl的上调与不良的预后和对治疗的抵抗有关。我们现在提供的初步证据表明，Axl是前列腺癌对多西紫杉醇耐药的关键驱动因素。虽然AXL基因的敲除以及药物AXL抑制剂对AXL的阻断使PCa细胞对多西紫杉醇敏感，但AXL过表达降低了多西紫杉醇在PCa细胞中的疗效。此外，我们证明，多西他赛耐药的PCa细胞的产生导致Axl表达上调，证实了Axl在多西他赛耐药中发挥关键作用的观点。因此，我们将验证我们的假设，即AXL激活导致对多西紫杉醇的耐药性 对PCa的治疗和对Axl的抑制将克服、延迟或防止PCa对多西紫杉醇的耐药性。因此，为了破译Axl在多西紫杉醇耐药中的确切作用，并开发一种新的治疗晚期PCa的策略，我们将确定Axl在多西紫杉醇和卡氮紫杉醇耐药的PCa细胞中的表达/活性的相关性，并进行临床前评估，以防止、延迟或克服雄激素受体阳性、雄激素敏感和去势抵抗的PCa移植瘤中的多西紫杉醇耐药。对AX1信号在多西紫杉醇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在诱导多西紫杉醇反应逃避中起关键作用。在特定的目标1中，我们将评估多西紫杉醇对Ax1表达缺失的多西紫杉醇耐药细胞系的增殖、迁移、侵袭和凋亡的影响。此外，我们将评估AXL抑制剂和多西紫杉醇对细胞的联合处理以及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紫杉醇敏感。在特定目的2中，对多西紫杉醇耐药的PCa移植瘤的临床前体内评估将确定AXL或药理学的靶向抑制AXL是否能够预防、延迟或克服多西紫杉醇耐药并增强多西紫杉醇的抗肿瘤效果。具体目标3将破译AXL调控耐药的确切分子机制和信号通路，最初的重点是NF-κB和MAPK级联反应和雄激素信号转导。AXL在PCa中作为多西紫杉醇和卡氮紫杉醇耐药的驱动因素的拟议研究有望导致一种更有效地治疗转移性PCa的创新的联合治疗方法。

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.