B55 alpha deficiency as a therapeutic target in cancer

项目总结 卵巢癌是女性癌症死亡的第五大原因。上皮性卵巢癌的总体5年生存率 卵巢癌(EOC)是最常见的类型，在过去的几十年里，大约有30%的人患有卵巢癌。高- 恶性浆液性卵巢癌(HGSOC)是最常见、最致命的卵巢上皮性癌。因此，新奇的战略 用于治疗HGSOC是迫切需要的。癌细胞通常带有基因缺陷，这些缺陷为 特定的目标。异源三聚体丝氨酸/苏氨酸调节亚基B55α的表达 在46%的卵巢癌中，由于杂合性丧失，磷酸酶PP2A降低。我们最近的小说 全基因组合成致死性筛查发现B55α减少导致细胞敏感性增强 涉及一种靶向复制应激反应激酶CHK1的抑制剂。目前，CHK1及其上游的抑制剂 效应器ATR正在进行临床试验，没有生物标志物的精确指导来识别响应 这会显著降低这些制剂的药效。因此，此应用程序的目标是 ATR/CHK1抑制剂靶向B55α缺陷型HGSOC和B55α的分子基础 一种生物标记物来指导这些制剂的使用。PP2A具有多种功能，包括对PP2A的负性调节 大量的致癌信号。癌基因激活可能会导致复制压力，这可能会对细胞造成致命的影响。 ATR/CHK1信号将复制应激抑制到毒性较低的水平。因此，癌细胞数量增加 复制应激，如具有c-Myc激活/表达的癌细胞，严重依赖ATR/CHK1生存。 鉴于PP2A在负调控多条致癌途径中的作用，B55α缺陷可能导致 癌基因激活和复制应激，使这些细胞对ATR/CHK1抑制敏感。我们 假设ATR和CHK1抑制剂通过促进B55α缺陷HGSOC细胞特异性靶向 复制压力。因此，B55α表达的降低可能成为指导ATR和CHK1使用的生物标志物 抑制剂。提出了三个具体目标。在目标1中，我们将确定c-myc在B55α缺陷中的作用- 诱导复制应激。在目标2中，我们将确定B55α缺乏诱导复制的原因 压力。在目标3中，我们将评估针对B55α缺陷的ATR和CHK1抑制的抗肿瘤活性 HGSOC细胞。如果成功，我们的研究将对提高卵巢癌的存活率产生重大影响 通过识别新的治疗方法和通过提供新的分层生物标志物来识别患者 ATR/CHK1抑制剂敏感人群。

PROJECT SUMMARY Ovarian cancer is the 5th leading cause of cancer death in women. The overall 5-year survival rate for epithelial ovarian cancer (EOC), the most common type, remains approximately 30% over the last several decades. High- grade serous ovarian cancer (HGSOC) is the most common and lethal form of EOC. Thus, the novel strategies for treating HGSOC are urgently needed. Cancer cells often carry genetic defects that provide opportunities for specific targeting. Expression of the B55 α, a regulatory subunit of the heterotrimeric serine/threonine phosphatase PP2A, is reduced in 46% of ovarian cancers, as a result of loss of heterozygosity. Our recent novel genome-wide synthetic lethality screen discovered that B55 α reduction led to the enhanced sensitivity of cells to an inhibitor targeting replication stress response kinase CHK1. Currently, inhibitors of CHK1 and its upstream effector ATR are being tested in clinical trials without precise guidance of biomarkers to identify responsive populations, which significantly reduce the efficacy of these agents. Thus, the goal of this application is to establish the molecular basis for targeting B55 α defective HGSOC by ATR/CHK1 inhibitors and for B55 α being a biomarker to guide the use of those agents. PP2A has diverse functions, including the negative regulation of numerous oncogenic signaling. Oncogene activation can cause replication stress that could be lethal to the cells. ATR/CHK1 signaling suppresses replication stress to less toxic levels. Thus, cancer cells with increased replication stress, such as cancer cells with c-Myc activation/expression, heavily rely on ATR/CHK1 for survival. Given the role of PP2A in negatively regulating multiple oncogenic pathways, B55 α deficiency may lead to oncogene activation and replication stress, rendering these cells sensitive to ATR/CHK1 inhibition. We hypothesize that ATR and CHK1 inhibitors specifically target B55 α-defective HGSOC cells by enhancing replication stress. Thus, reduced B55 α expression could be a biomarker to guide the use of ATR and CHK1 inhibitors. Three Specific Aims are proposed. In Aim 1, we will determine the role of c-Myc in B55 α deficiency- induced replication stress. In Aim 2, we will determine the causes of the B55 α deficiency-induced replication stress. In Aim 3, we will assess the anti-tumor activities of ATR and CHK1 inhibition in targeting B55 α defective HGSOC cells. If successful, our study will have a significant impact on improving the survival of ovarian cancer patients by identifying new treatment approaches and by providing a new stratification biomarker for identifying ATR/CHK1 inhibitor sensitive populations.