Targeting the metabolic vulnerabilities of patient-derived drug resistant tumors

项目摘要 晚期非小细胞肺癌仍然是一种不治之症，至少在一定程度上是由于干细胞样、 癌症起始细胞(CSCs)在常规治疗中存活并重新点燃治疗后复发和 转移性扩散。这一提议将检验线粒体柠檬酸盐载体Slc25a1， 作为NSCLC对不同治疗药物产生抗药性的关键代谢中心。考虑到 突变的遗传谱在治疗过程中继续进化，新出现的突变 对于目前可用的药物，可能并不总是具有靶向性。因此，有效的治疗方法的发展 不管肿瘤的突变情况如何，都是一个吸引人的概念。我们最近已经证明SLC25A1 促进CSC的扩张和自我更新，通过促进 柠檬酸对线粒体的进入导致线粒体代谢和氧化 磷酸化。当前项目的范围是确定耐药的代谢特征 病人来源的肿瘤。我们的初步数据显示，对表皮生长因子抑制剂的抗药性 受体、EGFR或对铂类药物的治疗涉及向SLC25A1驱动的转换和依赖 伴随着茎的表型诱导的线粒体代谢。因此，CTPI-2是人工合成的 与顺铂或EGFR抑制剂联合治疗致死性药物并在体外和体外恢复对这些药物的敏感性 活着。此外，我们提供了SLC25A1诱导干扰素I型(IFN-I)抗病毒先天免疫的证据 反应，可能是由氧化应激和线粒体DNA(MtDNA)在细胞质中的积累驱动的。 我们将这一信号与SLC25A1诱导的治疗耐药表型联系起来。考虑到这一点，的范围 目前的项目是测试SLC25A1允许耐药细胞存活的假设 治疗攻击处于能量有利的状态，肿瘤对不同类型药物的耐药性依赖于 根据SLC25A1驱动的常见代谢性状。其次，我们将澄清干扰素-I是否与药物有关 SLC25A1驱动的抗性表型。在目标1中，我们将使用一种新开发的有机系统，该系统允许 患者原发肿瘤的扩大以确定SLC25A1是否驱动不同类型的 耐药性不受主要驱动因素突变的影响。在目标2中，我们将确定组件是否 新发现的SLC25A1-mtDNA-干扰素-I环负责诱导茎的表型和 对主要作用于高增殖细胞的药物不敏感。总而言之，这些研究将提供 在揭示非小细胞肺癌发病机制方面的重大进展将填补知识空白 阐明线粒体、茎和耐药性之间意想不到的机械联系，我们 最终将有望为这种致命疾病的治疗打开新的治疗机会。

Project Summary Advanced NSCLC still remains an incurable disease, at least in part due to resilient populations of stem-like, cancer initiating cells (CSCs) that survive conventional therapies and reignite post-therapy relapse and metastatic dissemination. This proposal will test the hypothesis that the mitochondrial citrate carrier, Slc25a1, acts as a key metabolic hub through which NSCLC acquire resistance to different therapeutic agents. Given that the genetic spectrum of mutations continues to evolve during the course of therapy, newly emerging mutations may not always be targetable with currently available drugs. Thus, the development of therapies that act regardless of the mutational profile of tumors is an attractive concept. We have recently shown that Slc25a1 promotes CSC expansion and self-renewal, enhancing the energetic output of this population by promoting the mitochondrial entry of citrate with consequent induction of mitochondrial metabolism and oxidative phosphorylation. The scope of the current project is to identify the metabolic hallmarks of drug resistance in patient-derived tumors. Our preliminary data show that resistance to inhibitors of the Epidermal Growth Factor Receptor, EGFR or to platinum therapy involves a switch- and a dependency- towards Slc25a1-driven mitochondrial metabolism accompanied by the induction of a stemness phenotype. Hence, CTPI-2 is synthetic lethal with cisplatin or with EGFR inhibitor co-treatment and restores sensitivity to these agents in vitro and in vivo. Further, we provide evidence that Slc25a1 induces an Interferon type I (IFN-I) anti-viral innate immune response, likely driven by oxidative stress and by accumulation of mitochondrial DNA (mtDNA) in the cytoplasm. We link this signature to the therapy resistance phenotype induced by Slc25a1. With this in mind, the scopes of the current project are to test the hypothesis that Slc25a1 allows drug-resistant cells to endure and survive therapeutic attacks in an energetically favorable state and that tumors resistant to different types of drugs rely upon common metabolic traits driven by Slc25a1. Second, we will clarify whether IFN-I is involved in the drug resistant phenotype driven by Slc25a1. In Aim 1 we will use a newly developed organoid system that allows for the expansion of primary tumors derived from patients to determine whether Slc25a1 drives different types of drug resistance independently of the primary driver mutations. In Aim 2 we will determine whether components of the newly identified Slc25a1-mtDNA-IFN-I loop are responsible for induction of the stemness phenotype and the insensitivity to drugs that act predominantly on highly proliferating cells. Together, these studies will provide a major advance in enlightening novel mechanisms underlying NSCLC pathogenesis, will fill a gap in knowledge elucidating unexpected mechanistic links between the mitochondria, stemness and drug-resistance, which we will ultimately hope will open new therapeutic opportunities for the treatment of this deadly disease.