Targeting Defective DNA Damage Response Pathways in IDH1/2-mutant AML

两个关键代谢基因异柠檬酸脱氢酶-1和异柠檬酸脱氢酶-2(IDH1/2)的杂合突变是 在新诊断的AML患者中，高达20%的患者存在这种情况。IDH1/2酶将异柠檬酸转化为α-酮戊二酸 三羧酸(TCA)循环中的AKG。IDH1/2突变赋予新形酶活性，导致 AKG转化为肿瘤代谢物2-羟基戊二酸(2HG)。2HG竞争性抑制AKG- 依赖的双加氧酶，导致深刻的表观遗传学改变和造血功能受损 差异化。IDH1/2抑制剂现在被FDA批准用于AML，尽管这些药物通常不是 治愈，完全缓解率(CR)和中位总存活率(OS)在20%-30%和 分别为8-12个月。此外，对突变型IDH1/2抑制剂的原发和获得性耐药性通常 发生。这些药物无法作为单一疗法治愈的部分原因可以归因于他们的 作用机制。具体地说，这些药物通过诱导分化以细胞抑制的方式发挥作用， 突显的是，突变的IDH1/2克隆在大多数患者中持续存在，即使是那些 录像机。这些数据强调了开发针对IDH1/2突变AML的替代方法的必要性。 我们的团队最近发现IDH1/2突变会导致DNA损伤反应(DDR)缺陷，这种缺陷 对聚(ADP)-核糖聚合酶(PARP)抑制剂具有敏感性。从机制上讲，我们证明了 2HG诱导的赖氨酸去甲基酶KDM4B的抑制导致组蛋白3异常高甲基化 赖氨酸9(H3K9)在DNA断裂周围的基因座上，掩盖了局部H3K9三甲基化信号，这是 正确执行同源重组(HR)，这是DNA双链断裂(DSB)修复的关键 路径。我们还将这些发现扩展到其他TCA基因突变，这些突变会产生肿瘤代谢产物， 我们统称为“肿瘤代谢物诱导的BRCess”。我们的研究表明，肿瘤性代谢- 诱导的BRCAness是肿瘤类型不可知的，我们现在正在将这项工作直接转化为多个临床 目前正在测试PARP抑制剂对包括AML在内的IDH1/2突变癌症的疗效的试验 (NCT03953898；The Prime Trial；PI：Prebet)。 现在公认的是，IDH1/2突变会导致AML的DDR缺陷，在这里，我们建议 研究：(A)急性髓系白血病中常见的共生突变对相关的DDR缺陷的影响，这将是 对治疗靶向至关重要；(B)哪种DDR抑制剂将最有效，以及与 治疗AML的其他系统性药物将提高疗效；以及(C)我们的DDR抑制剂在多大程度上 这些策略将对对治疗具有内在或获得性耐药的肿瘤有效。这些研究已经 为新诊断和复发的IDH1/2建立全新治疗方法的可能性- 突变体AML，它利用了我们团队发现的DDR缺陷。通过专注于FDA- 无论是获得批准还是处于临床试验阶段，我们的工作都可以迅速转化为临床。

Heterozygous mutations in two key metabolic genes, isocitrate dehydrogenase-1 and -2 (IDH1/2), are present in up to 20% of newly diagnosed AML patients. IDH1/2 enzymes convert isocitrate to a-ketoglutarate (aKG) in the tricarboxylic acid (TCA) cycle. IDH1/2 mutations impart a neomorphic enzyme activity, leading to the conversion of aKG to the oncometabolite, 2-hydroxyglutarate (2HG). 2HG competitively inhibits aKG- dependent dioxygenases, which induces profound epigenetic alterations and impaired hematopoietic differentiation. IDH1/2 inhibitors are now FDA-approved for AML, although these agents typically are not curative, with complete response (CR) rates and median overall survival (OS) ranging between 20-30% and ~8-12 months, respectively. In addition, primary and acquired resistance to mutant IDH1/2 inhibitors commonly occurs. The inability to achieve a cure with these drugs as a monotherapy in part can be attributed to their mechanism of action. Specifically, these drugs act in a cytostatic manner via the induction of differentiation, which is highlighted by persistence of mutant IDH1/2 clones in the majority of patients, even those who achieve a CR. These data underscore the need to develop alternative approaches to target IDH1/2-mutant AML. Our team recently discovered that IDH1/2 mutations induce a DNA damage response (DDR) defect which confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors. Mechanistically, we demonstrated that 2HG-induced inhibition of the lysine demethylase, KDM4B, results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of homologous recombination (HR), a key DNA double-strand break (DSB) repair pathway. We also extended these findings to other TCA gene mutations which create oncometabolites, which we have collectively termed “oncometabolite-induced BRCAness”. Our work suggests that oncometabolite- induced BRCAness is tumor type-agnostic, and we are now directly translating this work into multiple clinical trials, which currently are testing the efficacy of PARP inhibitors against IDH1/2-mutant cancers, including AML (NCT03953898; the PRIME trial; PI: Prebet). It is now well-established that IDH1/2 mutations induce DDR defects in AML, and here we propose to study: (a) the impact of common, co-occurring mutations in AML on the associated DDR defect, which will be critical for therapeutic targeting; (b) which DDR inhibitors will be most effective, and whether combinations with other systemic agents in AML will increase efficacy; and (c) the extent to which our DDR inhibitor-based strategies will be effective against tumors with intrinsic or acquired resistance to therapy. These studies have the potential to establish an entirely new therapeutic approach for newly diagnosed and relapsed IDH1/2- mutant AML, which exploits DDR defects identified by our team. By focusing on drugs which are either FDA- approved or in clinical trials, our work can be rapidly translated into the clinic.