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

三阴性乳腺癌中能量重编程调节的肿瘤途径和耐药性

• 批准号: 10738335
• 负责人: Benny Abraham Kaipparettu
• 金额: $ 6.33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10738335
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Aftercare; Autophagocytosis; Benign; Binding; Bioinformatics; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Carrier Proteins; Cell model; Cells; Characteristics; Citrates; Citric Acid Cycle; Clinical; Clinical Data; Clinical Trials; Coenzyme A; Combined Modality Therapy; Communication; Cytoplasm; Dasatinib; Data; Dependence; Drug Combinations; Drug Targeting; Drug resistance; Enzymes; FDA approved; Fatty Acids; Generations; Glycine; Glycolysis; Goals; In Vitro; Invaded; Lipids; MEKs; Malignant Neoplasms; Mechanics; Mediating; Membrane; Messenger RNA; Mitochondria; Modeling; Modification; Myristates; Myristic Acylation Site; N-Myristoylation; N-myristoyltransferase; N-terminal; NMT2 gene; Neoplasm Metastasis; Nuclear; Oncogenic; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phase Ib/II Trial; Phosphotransferases; Population; Primary Neoplasm; Prognosis; Property; Proteins; Publishing; Reactive Oxygen Species; Recurrence; Regulation; Reporting; Research; Resistance; Role; SRC gene; Severities; Signal Pathway; Signal Transduction; System; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; breast cancer progression; cancer subtypes; citrate carrier; clinical translation; drug resistance development; hormone receptor-negative; hormone receptor-positive; in vivo; inhibitor; inhibitor therapy; mRNA Expression; malignant breast neoplasm; metabolomics; multiple omics; myristoylation; novel; novel therapeutic intervention; oxidation; palmitoylation; patient derived xenograft model; preclinical study; resistance mechanism; response; src-Family Kinases; targeted treatment; translational approach; translational potential; treatment strategy; triple-negative invasive breast carcinoma; tumor

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.

翻译后摘要：与其他亚型的乳腺癌（BC），基础或三阴性（TN）BC遭受穷人 预后，由对驱动信号通路的有限理解引起。因此，对于TNBC， 从目前可用的靶向治疗是有限的，迫切需要新的治疗策略。丕的 实验室使用了一个研究管道，利用transmitochondrial cybrid（cybrid）模型。Cybrid系统是 优秀的细胞模型，允许比较来自不同细胞的线粒体（例如：良性和TNBC细胞 具有不同的侵袭/转移潜能）。我们应用多个OMIC 在胞质杂种模型中发现线粒体-核通讯和线粒体能量的方法 重编程调节癌症通路。利用这一研究渠道，我们最近发表了 转移性TNBC对线粒体脂肪酸β-氧化（FAO）具有高度的能量依赖性。我们还 发现FAO是TNBC中Src oncopathway的关键调节者。我们验证了赛伯人的发现 亲本BC细胞中的模型、PDX模型和临床数据。原癌基因c-Src是一种 通常在TNBC中上调癌症途径。然而，包括我们自己的试验在内的多项临床试验 显示Src抑制剂的单一药物方法在NSCLC患者中仅具有有限的临床益处。 因此，重要的是理解TNBC中c-Src的活化和耐药性的机制，以减少TNBC中c-Src的表达。 开发可靠的治疗策略，以抑制TNBC进展。N-肉豆蔻酰化是一种脂质修饰， 将脂肪酸肉豆蔻酸酯连接到靶蛋白的N末端甘氨酸残基上。我们的初步 对胞质杂种模型和亲本细胞的分析表明，FAO通过增强c-Src的肉豆蔻酰化来调节c-Src的肉豆蔻酰化， 肉豆蔻酰CoA的胞质利用度。在这个项目中，我们将验证这一有趣的发现，使用系统 调整FAO途径。由于Src抑制剂治疗TNBC后频繁发生耐药性，我们 还分析了FAO或Src抑制剂治疗TNBC的潜在耐药机制。我们 强有力初步数据表明，对FAO或Src抑制的耐药性是由于自噬介导的 肿瘤存活受活性氧（ROS）诱导的MEK/ERK通路调节。因此，这 项目还将使用多种研究方法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，我们提出了大规模的临床前研究，使用多种PDX TNBC模型，以确定联合药物策略克服FAO或Src耐药性的益处 TNBC中的抑制疗法。总的来说，这一建议是非常重要的，因为它预计将1）揭示 线粒体串扰在TNBC中Src信号传导活化中的意义，以及2）开发策略， 将现有FDA批准的Src靶向药物与合适的联合治疗重新用于快速临床 翻译，以管理目前非针对性的TNBC。

项目成果

A mechanistic modeling framework reveals the key principles underlying tumor metabolism.

机械建模框架揭示了肿瘤代谢的基础关键原理。

• DOI: 10.1371/journal.pcbi.1009841
• 发表时间: 2022-03
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Tripathi S;Park JH;Pudakalakatti S;Bhattacharya PK;Kaipparettu BA;Levine H
• 通讯作者: Levine H