Energy reprogramming-regulated oncopathways and drug resistance in triple negative breast cancer

摘要：与乳腺癌的其他亚型相比，基底或三阴性乳腺癌的发病率较低。 预后，是由于对驾驶员信号通路的有限了解造成的。因此，对于TNBC来说，临床益处 目前可获得的靶向治疗方法有限，迫切需要新的治疗策略。圆周率 Lab使用了一条研究管道，该管道利用了传递线粒体半胱氨酸(Cybrid)模型。塞布里德系统是一种 优秀的细胞模型，允许比较不同细胞的线粒体(例如：良性细胞和TNBC细胞 具有不同的侵袭/转移潜力)在共同定义的核背景中。我们应用了多重组学 线粒体核-核通讯和线粒体能量的研究进展 对受调控的癌症通路重新编程。利用这一研究渠道，我们最近发表了 转移性肿瘤细胞对线粒体脂肪酸β氧化反应具有高度的能量依赖性。我们还有 发现粮农组织是TNBC中SRC的关键监管者。我们验证了来自Cybrid的发现 亲代BC细胞模型、PDX模型和临床数据。原癌基因c-Src是最常见的 在TNBC中普遍上调了癌症通路。然而，包括我们自己的试验在内的多项临床试验 在未经选择的TNBC患者中，单一药物治疗仅显示出有限的临床益处。 因此，了解c-Src在TNBC中的激活和耐药机制对临床治疗有重要意义。 制定可靠的治疗策略以抑制TNBC的进展。N-肉豆蔻酰化是一种脂类修饰， 目标蛋白质的N-末端甘氨酸残基上的脂肪酸肉豆蔻酸酯的结合。我们的预赛 对Cybrid模型和亲本细胞的分析表明，FAO通过增强 肉豆蔻醇辅酶A的胞浆利用率。在这个项目中，我们将使用系统验证这一有趣的发现 粮农组织途径的调控。由于在TNBC中应用Src抑制剂治疗后出现频繁的耐药性，我们 还分析了粮农组织或Src抑制剂治疗TNBC的潜在耐药机制。我们的 强有力的初步数据表明，对FAO或Src抑制的耐药性是由自噬介导的 由活性氧(ROS)诱导的MEK/ERK通路调节的肿瘤生存。因此，这一点 该项目还将使用多种研究方法来验证这一令人兴奋的机制。考虑到我们强大的 在体外和体内的初步数据中，我们建议使用多个PDX进行大规模的临床前研究 确定联合用药策略的益处以克服对FAO或Src耐药性的TNBC模型 TNBC中的抑制治疗。总体而言，这项建议意义重大，因为预计它将揭示 线粒体串扰在TNBC中Src信号激活中的意义和2)制定策略以 将现有FDA批准的Src靶向药物与适当的联合疗法重新用于快速临床 翻译以管理目前非目标的TNBC。

Abstract: Compared to other subtypes of breast cancers (BC), basal or triple negative (TN) BC suffers a poor prognosis, caused by limited understanding of the driver signaling pathways. Thus, for TNBC, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. PI's lab uses a research pipeline that utilizes transmitochondrial cybrid (cybrid) models. Cybrid system is an excellent cell model that allows comparing mitochondria from different cells (example: benign and TNBC cells with varying invasion/metastatic potential) in a common defined nuclear background. We apply multiple OMICs approaches in cybrid models to discover mitochondria-nuclear communication and mitochondrial energy reprogramming regulated cancer pathways. Using this research pipeline, we have recently published that metastatic TNBC has high energy-dependence to mitochondrial fatty acid β-oxidation (FAO). We have also discovered that FAO is a critical regulator of Src oncopathway in TNBC. We validated the findings from cybrid models in parental BC cells, PDX models and clinical data. Proto-oncogene c-Src is one of the most commonly upregulated cancer pathways in TNBC. However, multiple clinical trials including our own trial showed only limited clinical benefit with single drug approach of Src inhibitors in unselected TNBC patients. Thus, it is important to understand the mechanism of activation and drug resistance of c-Src in TNBC to develop reliable treatment strategies to inhibit TNBC progression. N-myristoylation is a lipid modification with the attachment of a fatty acid, myristate, onto the N- terminal glycine residue of target proteins. Our preliminary analysis in cybrid models and parental cells suggest that FAO regulates myristoylation of c-Src by enhancing cytosolic availability of myristoyl CoA. In this project we will validate this interesting finding using systematic modulation of FAO pathway. Since frequent drug resistance occurs after Src inhibitor therapy in TNBC, we have also analyzed the potential drug resistance mechanisms for FAO or Src inhibitor therapy in TNBC. Our strong preliminary data suggest that drug resistance to FAO or Src inhibition is due to autophagy-mediated tumor survival that is regulated by the reactive oxygen species (ROS)-induced MEK/ERK pathway. Thus, this project will also validate this exciting mechanism using multiple research approaches. Considering our strong in vitro and in vivo preliminary data, we have proposed large-scale preclinical studies using multiple PDX TNBC models to determine benefit of combination drug strategy to overcome the resistance to FAO or Src inhibition therapy in TNBC. Overall, this proposal is highly significant as it is expected to 1) reveal the significance of mitochondrial crosstalk in the activation of Src signaling in TNBC and 2) develop strategies to repurpose the existing FDA approved Src targeting drugs with suitable combination therapy for rapid clinical translation to manage currently non-targetable TNBC.