Overcoming in vivo resistance to chemotherapy in triple-negative breast cancer

摘要 三阴性乳腺癌(TNBC)是乳腺癌(BC)中最具侵袭性的亚型，没有靶向 目前尚有治疗选择，主要依靠常规化疗。然而，TNBC患者往往 在治疗过程中产生化疗耐药性。新型“可用药”介体的鉴定 TNBC中化疗耐药的减少有可能改善化疗耐药的TNBCs的治疗。 最近的研究表明，染色体不稳定、核因子B信号异常、DNA突变的比率很高 修复酶，药物转运蛋白表达改变，更大的药物解毒和 调控细胞凋亡的基因作为TNBC化疗耐药机制。除了这些细胞固有特性之外 机制方面，细胞外基质(ECM)作为肿瘤微环境的主要成分可能发挥着重要的作用。 多方面在TNBC化疗耐药中的作用然而，对ECM的研究大多是在这样的背景下进行的 乳腺癌的转移而不是耐药。这项建议是基于我们最近的发现， 低氧诱导赖氨酰氧化酶(LOX：一种细胞外基质重塑因子)促进化疗药物的耐药性 (蒽环类和紫杉烷类)通过高激活整合素信号在TNBC中发挥作用。此外，LOX的抑制作用 其表达或活性与化疗药物协同作用，克服TNBCs的耐药。 此外，除了已知的细胞外LOX(成熟形式)的矩阵重新建模功能外，我们还 发现了可能调节转录的LOX(前蛋白LOX形式)的核定位。目标1是 阐明LOX对整合素信号的调控机制并探讨其在体内的作用 体外和体内TNBCs的化疗耐药性。目标2是执行高通量筛选(HTS) 使用LOX活性测定的多样化化合物文库和使用药效团模型的电子筛选 寻找新的脂氧合酶抑制剂。然后将使用蛋白水解靶向嵌合分子(PROTAC)方法 以产生能降解LOX的化合物。不同类型的LOX抑制剂作为增敏剂的潜力 将对不同的化疗药物进行研究。目标3是测试LOX抑制剂与 具有转录特征的患者来源异种移植(PDX)模型中的化疗药物 肿瘤的异质性和来源于PDX的器官样物质。这项研究的最终目标是开发一种 化疗药物与有效和选择性的LOX抑制剂的结合将为 提高TNBC患者的化疗疗效和生存率。

ABSTRACT Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with no targeted therapy options yet available and relying primarily on conventional chemotherapy. However, TNBC patients often develop chemotherapy resistance during the course of treatment. Identification of novel “druggable” mediators of chemotherapy resistance in TNBC has potential to improve the treatment of chemotherapy-resistant TNBCs. Recent studies revealed a high rate of chromosomal instability, aberrant NF B signaling, mutations in DNA repair enzymes, altered expression of drug transporter proteins, greater drug detoxification and imbalance of genes regulating apoptosis as chemotherapy resistance mechanisms in TNBC. In addition to these cell intrinsic mechanisms, the extracellular matrix (ECM) being a major component of tumor microenvironment may play a multifaceted role in chemotherapy resistance in TNBC. However, ECM has been studied mostly in the context of metastasis rather than drug resistance in breast cancer. This proposal is based on our recent findings that hypoxia-induced lysyl oxidase (LOX: an ECM re-modeler) promotes resistance to chemotherapeutic agents (anthracyclines and taxanes) in TNBC by hyperactivating integrin signaling. In addition, inhibition of LOX expression or its activity synergizes with chemotherapeutic agents and overcomes therapy resistance in TNBCs. Furthermore, in addition to the known matrix re-modeling function of LOX (mature form) outside the cell, we discovered nuclear localization of LOX (pre pro-protein LOX form) potentially regulating transcription. Aim 1 is to elucidate the mechanism of integrin signaling regulation by LOX and to investigate its contribution to chemoresistance in TNBCs both in vitro and in vivo. Aim 2 is to perform a high-throughput screen (HTS) of a diversified compound library using a LOX activity assay and an in silico screen using a pharmacophore model to identify novel inhibitors of LOX. Proteolysis targeting chimeric molecule (PROTAC) approach will then be used to generate LOX-degrading compounds. The potential of different types of LOX inhibitors as sensitizers to different chemotherapeutic agents will be investigated. Aim 3 is to test LOX inhibitors in combination with chemotherapeutic agents in transcriptionally-characterized patient derived xenograft (PDX) models representing tumor heterogeneity and organoids derived from the PDXs. The ultimate goal of this study is to develop a combination of chemotherapeutic agents with potent and selective LOX inhibitors that will pave the way towards improving the efficacy of chemotherapy and survival of TNBC patients.