NAD+ metabolism in PARP inhibitor resistance of ovarian cancer

项目摘要/摘要 高级别浆液性卵巢癌(HGSOC)仍然是卵巢癌中最致命的形式，部分原因是 大多数患者会出现对包括铂类药物在内的标准治疗耐药的复发性疾病。Poly(ADP- 核糖)聚合酶(PARP)抑制剂(PARPis)最近被批准作为一种重要的治疗方法 同源重组(HR)DNA修复缺陷的HGSOC，尤其是由于 BRCA1或BRCA2的突变。然而，70%以上最初对PARPis有反应的HGSOC后来发展起来 抵抗力强的疾病。不幸的是，PARPI耐药的潜在机制尚不清楚。这 该项目旨在了解获得性PARPI耐药机制和相关的治疗 HR缺陷HGSOC中的漏洞。我们利用HR缺陷型HGSOC细胞株和 患者来源的异种移植(PDX)模型显示获得性PARPI抵抗与高水平的 烟酰胺单核苷酸腺苷转移酶1(NMNA1)。我们的结果还表明，NMNA1 上调导致NAD+水平增加，从而恢复HR并创造独特的代谢 PARPI抗性细胞中的依赖性。这些发现导致了我们的中心假设，即HR缺陷的HGSOC 通过上调NMNA1获得PARPI抗性，NMNA1可诱导NAD+水平，从而导致心率恢复 导致代谢依赖，这种依赖可能在治疗上是可以治愈的。在强劲的初步数据的指引下， 我们提出三个具体目标：1)研究NMNA1在HGSOC细胞中是如何上调的；2)确定如何 NMNA1诱导PARPI耐药；3)检测NMNA1是否诱导PARPI代谢依赖。 在HGSOC的临床前模型中，耐药肿瘤可以作为靶点。这些研究将揭示一个以前的 HGSOC细胞对PARPis产生抗性的机制未知，并可能识别一种潜在的新的 耐PARPI的HGSOC的治疗选择。拟议的工作是迈向我们的 为HGSOC患者开发有效治疗的长期目标。

PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSOC) remains the deadliest form of ovarian cancer, in part because most patients develop recurrent disease that is resistant to standard treatment, including platinum. Poly(ADP- ribose) polymerase (PARP) inhibitors (PARPis) have recently been approved as an important therapy for HGSOCs, especially for HGSOCs with defects in homologous recombination (HR) DNA repair due to mutations in BRCA1 or BRCA2. However, over 70% HGSOCs that initially respond to PARPis later develop resistant disease. Unfortunately, the underlying mechanisms of PARPi resistance are poorly understood. This project is designed to understand acquired PARPi resistance mechanisms and associated therapeutic vulnerabilities in HR-defective HGSOC. Our preliminary studies using HR-deficient HGSOC cell lines and patient derived xenograft (PDX) models show that acquired PARPi resistance is associated with high levels of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1). Our results also show that NMNAT1 upregulation results in an increase in NAD+ levels, which restores HR and creates a unique metabolic dependency in PARPi-resistant cells. These findings led to our central hypothesis that HR-deficient HGSOC acquire PARPi resistance by upregulating NMNAT1 that induces NAD+ levels leading to HR restoration as well as causing a metabolic dependency that may be therapeutically tractable. Guided by strong preliminary data, we propose three specific aims to: 1) examine how NMNAT1 is upregulated in HGSOC cells; 2) determine how NMNAT1 induces PARPi resistance; and 3) test whether NMNAT1-induced metabolic dependency in PARPi- resistant tumors can be targeted in preclinical models of HGSOC. These studies will unveil a previously unknown mechanism by which HGSOC cells become resistant to PARPis and may identify a potential new therapeutic option for PARPi-resistant HGSOC. The proposed work comprises an essential step toward our long-term goal of developing effective therapy for patients with HGSOC.