Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancer

 描述（由申请人提供）：上皮性卵巢癌（EOC）是美国妇科恶性肿瘤中的主要死亡原因。在所有EOC亚型中，卵巢透明细胞癌（OCCC）在晚期诊断时预后最差，目前尚无有效的治疗方法。ARID 1A是表观遗传SWI/SNF染色质重塑子的亚基，是在许多癌症类型中显示出最高突变率的基因之一。事实上，ARID 1A基因是OCCC中突变最高的基因，发生在超过50%的病例中。目前提案的最终目标是开发治疗和根除这种毁灭性疾病的新方法。由于ARID 1A是OCCC中最高突变的基因，我们进行了无偏筛选，并证明在ARID 1A突变的OCCC中，另一种表观遗传调节因子EZH 2的抑制是合成致死的。观察到的合成致死性是由于ARID 1A和EZH 2在调节同一组靶基因的表达中发挥的拮抗作用。PI 3 K/AKT信号传导的抑制有助于观察到的合成致死率。有趣的是，ARID 1A突变通常与 PIK 3CA基因突变。除了EZH 2，我们未探索的数据表明，ARID 1A突变的OCCC细胞也对HDAC 2的抑制选择性敏感。ARID 1A突变与TP 53突变是互斥的，并且ARID 1A突变损害p53靶基因的表达。然而，ARID 1A调节p53活性的机制从未被探索过。我们的初步数据表明，ARID 1A突变与肌球蛋白IIa（MyoIIa）与SWI/SNF复合物以ARID 1A状态依赖性方式相关。MyoIIa是一种已知的肿瘤抑制因子，是p53活性所必需的。因此，这些研究表明，ARID 1A突变通过MyoIIa隔离损害p53活性。我们的中心假设是，ARID 1A突变的OCCC可以通过靶向我们所涉及的四种蛋白质（即EZH 2，HDAC 2，PI 3 K和p53）来治疗并最终根除。因此，提出了三个具体目标：目标1：研究HDAC 2在观察到的ARID 1A和EZH 2之间的合成致死性和基因表达拮抗作用中的作用;目标2。研究ARID 1A通过MyoIIa和Aim 3调节p53活性的机制。为ARID 1A突变的治疗提供新的策略。拟议的研究具有高度创新性，因为它们挑战了当前的研究/临床范式，为表观遗传疗法提供了新的概念，并利用创新方法探索ARID 1A突变OCCC的新干预策略。这项研究具有很高的影响力，因为它有可能为OCCC建立第一个有效的靶向治疗策略。由于SWI/SNF染色质重塑复合物组分的遗传改变发生在超过20%的人类癌症中，因此从目前研究中获得的机制见解也将对许多不同类型的癌症产生广泛的影响。

 DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in the United States. Among all EOC subtypes, ovarian clear cell carcinoma (OCCC) carries the worst prognosis when diagnosed at an advanced stage and there is currently no effective therapy for this disease. ARID1A, a subunit of the epigenetic SWI/SNF chromatin remodeler, is among the genes that show the highest mutation rates across many cancer types. In fact, the ARID1A gene is the highest mutated gene in OCCC that occurs in over 50% of the cases. The ultimate goal of the current proposal is to develop novel approaches to treat and eradicate this devastating disease. Since ARID1A is the highest mutated gene in OCCC, we performed an unbiased screen and demonstrated that in ARID1A mutated OCCC the inhibition of EZH2, another epigenetic regulator, is synthetically lethal. The observed synthetic lethality is due to antagonistic roles played by ARID1A and EZH2 in regulating the expression of the same set of target genes. Inhibition of PI3K/AKT signaling contributes to the observed synthetic lethality. Interestingly, ARID1A mutation typically co-exists with PIK3CA mutation in OCCC. In addition to EZH2, our unexplored data suggest that ARID1A-mutated OCCC cells are also selectively sensitive to inhibition of HDAC2. ARID1A mutation is mutually exclusive from TP53 mutation, and expression of p53 target genes is impaired by ARID1A mutation. However, the mechanism by which ARID1A regulates p53 activity has never been explored. Our preliminary data indicate that ARID1A mutation correlates with the association of myosin IIa (MyoIIa) with the SWI/SNF complex in an ARID1A status-dependent manner. MyoIIa is a known tumor suppressor that is necessary for p53 activity. Thus, these studies suggest that ARID1A mutation impairs p53 activity through MyoIIa sequestration. Our central hypothesis is that ARID1A-mutated OCCC can be treated and ultimately eradicated by targeting the four proteins (namely EZH2, HDAC2, PI3K and p53) we have implicated. Accordingly, three specific aims are proposed: Aim 1: To investigate the role of HDAC2 in the observed synthetic lethality and gene expression antagonism between ARID1A and EZH2; Aim 2. To investigate the mechanisms by which ARID1A regulates p53 activity through MyoIIa; and Aim 3. To develop novel therapeutic strategies for ARID1A mutation. The proposed studies are highly innovative because they challenge current research/clinical paradigms, contribute to new concepts for epigenetic therapeutics, and utilize innovative methods to explore new intervention strategies for ARID1A-mutated OCCC. The research proposed is of high impact because it has the potential to establish the first effective targeted therapeutic strategy for OCCC. Since genetic alterations in components of the SWI/SNF chromatin-remodeling complex occur in more than 20% of all human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.