B55 alpha deficiency as a therapeutic target in cancer

项目摘要 卵巢癌是女性癌症死亡的第五大原因。上皮癌的5年生存率 卵巢癌（EOC）是最常见的类型，在过去几十年中仍然保持约30%。高- 分级浆液性卵巢癌（HGSOC）是最常见和致命的EOC形式。因此，新战略 用于治疗HGSOC是迫切需要的。癌细胞通常携带遗传缺陷， 具体目标。异源三聚体丝氨酸/苏氨酸调节亚基B55 α的表达 磷酸酶PP 2A在46%的卵巢癌中减少，这是杂合性丢失的结果。我们最近的小说 全基因组合成致死筛选发现，B55 α减少导致细胞敏感性增强 涉及靶向复制应激反应激酶CHK 1的抑制剂。目前，CHK 1及其上游的抑制剂 效应ATR正在临床试验中进行测试，而没有生物标志物的精确指导来识别应答性ATR。 这大大降低了这些药物的疗效。因此，本申请的目标是 为ATR/CHK 1抑制剂靶向B55 α缺陷型HGSOC和B55 α被 一种生物标记物来指导这些药物的使用。PP 2A具有多种功能，包括负调节 许多致癌信号。癌基因激活可引起复制应激，这可能对细胞是致命的。 ATR/CHK 1信号转导抑制复制应激至毒性较低的水平。因此，癌细胞增加 复制应激，如具有c-Myc活化/表达的癌细胞，严重依赖ATR/CHK 1存活。 鉴于PP 2A在负调节多种致癌途径中的作用，B55 α缺乏可能导致 癌基因激活和复制应激，使这些细胞对ATR/CHK 1抑制敏感。我们 假设ATR和CHK 1抑制剂通过增强B55 α缺陷型HGSOC细胞的增殖而特异性靶向B55 α缺陷型HGSOC细胞， 复制应力因此，B55 α表达降低可能是指导ATR和CHK 1使用的生物标志物。 抑制剂的提出了三个具体目标。在目标1中，我们将确定c-Myc在B55 α缺乏中的作用- 诱导复制应激。在目标2中，我们将确定B55 α缺陷诱导复制的原因 应力在目的3中，我们将评估ATR和CHK 1抑制在靶向B55 α缺陷型细胞中的抗肿瘤活性。 HGSOC细胞。如果成功，我们的研究将对提高卵巢癌的生存率产生重大影响 通过确定新的治疗方法和提供新的分层生物标志物， ATR/CHK 1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.