Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancer

 描述(申请人提供)：卵巢上皮癌(EOC)是美国妇科恶性肿瘤的主要死亡原因。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。ARID1A是表观遗传的SWI/SNF染色质重构子的一个亚单位，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，ARID1A基因是OCCC中突变最高的基因，发生在50%以上的病例中。目前提案的最终目标是开发新的方法来治疗和根除这种毁灭性的疾病。由于ARID1A是OCCC中突变最高的基因，我们进行了无偏筛选，证明在ARID1A突变的OCCC中，另一种表观遗传调节因子EZH2的抑制是合成致死的。观察到的合成致死性是由于ARID1A和EZH2在调节同一组靶基因的表达方面发挥了拮抗作用。抑制PI3K/AKT信号转导有助于观察到的合成致死性。有趣的是，ARID1A突变通常是共存的 OCCC中存在PIK3CA突变。除了EZH2，我们未探索的数据表明，ARID1A突变的OCCC细胞也对HDAC2的抑制选择性敏感。ARID1A突变与TP53突变是互斥的，而p53靶基因的表达受ARID1A突变的影响。然而，ARID1A调节P53活性的机制从未被探索过。我们的初步数据表明，ARID1A突变与肌球蛋白IIa(MyoIIa)与SWI/SNF复合体的关联以ARID1A状态依赖的方式相关。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，ARID1A突变通过MyoIIa隔离损害了P53的活性。我们的中心假设是，通过靶向我们所涉及的四种蛋白(即EZH2、HDAC2、PI3K和P53)，ARID1A突变的OCCC可以被治疗并最终被根除。目的1：研究HDAC2在ARID1A和EZH2合成致死性和基因表达拮抗中的作用；目的2.研究ARID1A通过MyoIIa调节P53活性的机制；目的3.开发ARID1A突变的新治疗策略。拟议的研究具有很高的创新性，因为它们挑战了当前的研究/临床范式，为表观遗传学提供了新的概念，并利用创新的方法探索了对ARID1A突变的OCCC的新干预策略。提出的这项研究具有很高的影响力，因为它有可能建立第一个有效的OCCC靶向治疗策略。

 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.