CHEK2 loss promotes prostate cancer resistance to PARP inhibitors

摘要 转移性去势抵抗性前列腺癌（mCRPC）是一种无法治愈的疾病， 在美国，每年约有33,000人死亡。治疗选择有限， 延长生命的mCRPC患者。迫切需要开发新的靶向治疗，特别是 基于肿瘤基因组改变的个性化治疗。最近的基因组研究显示， 具有潜在基因组改变的多种可操作的分子靶标。值得注意的是， 参与DNA损伤反应的基因是最常见的遗传事件之一，并在mCRPC中富集。 这些改变与前列腺癌（PCa）细胞中的特定治疗脆弱性相关。 具体地说，同源重组（HR）修复的缺陷将预测对Poly抑制的敏感性。 （ADP-核糖）聚合酶（PARP）。PARP抑制剂（PARPis）是一种新型的靶向治疗药物， 通过阻止PARP酶修复肿瘤细胞中受损的DNA。brca 1和brca 2基因 编码HR修复所必需的蛋白质。缺乏BRCA 1/2的癌细胞依赖于PARP调节的 DNA修复，对PARPis高度敏感。美国FDA已经批准了两种PARP抑制剂（奥拉帕尼和 rucaparib）用于治疗具有有害BRCA 1/2或HR修复基因突变的mCRPC患者。 使用PARPis进行有效治疗的主要障碍之一是如何选择最有可能 从PARP抑制中获益。对PARPis的抗性也代表了一个可怕的临床问题。通过 全基因组CRISPR（成簇规则间隔短回文重复序列）筛选，我们最近 发现了许多介导细胞反应和抗PARP抑制的基因。没想到， 我们发现，CHEK 2（检查点激酶2），一种细胞周期检查点调节因子和肿瘤抑制因子的缺失， 基因，显著增加了PCa细胞对PARP抑制的抗性（而不是敏感性）。CHEK 2扮演一个角色 HR修复和CHEK 2改变目前用于预测奥拉帕尼在FDA批准的HR中的反应， 修复基因板。该项目的目标是确定CHEK 2的缺失在多大程度上使PCa细胞 抗PARP抑制，并在临床前PCa模型中定义潜在机制。完成时 在这个项目中，我们期望证明CHEK 2损失是预测PARPi抗性的生物标志物。的 这项研究的结果可能会改变患者接受PARP抑制的资格，并对未来的治疗产生积极影响。 临床实践

ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease that is expected to account for approximately 33,000 deaths each year in the United States. Therapeutic options are limited for mCRPC patients that extend life. There is an urgent need for developing novel targeted therapies, especially personalized therapies based on genomic alterations in tumors. Recent genomic studies have revealed a variety of actionable molecular targets with underlying genomic alterations. Notably, alterations in genes involved in DNA damage response are among the most common genetic events and enriched in mCRPC. These alterations have been correlated with particular therapeutic vulnerabilities in prostate cancer (PCa) cells. Specifically, defects in homologous recombination (HR) repair would predict sensitivity to inhibition of Poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) are a new type of targeted therapy, which works by preventing the enzyme PARP from repairing damaged DNA in tumor cells. The BRCA1 and BRCA2 genes encode proteins essential for HR repair. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are highly sensitive to PARPis. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for the treatment of mCRPC patients with deleterious BRCA1/2 or HR repair gene mutations. One of the major barriers to effective treatment using PARPis is how to select patients who most likely benefit from PARP inhibition. Resistance to PARPis also represents a formidable clinical problem. Through genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screens, we recently discovered a number of genes that mediate cellular response and resistance to PARP inhibition. Unexpectedly, we found that loss of CHEK2 (Checkpoint kinase 2), a cell cycle checkpoint regulator and tumor suppressor gene, significantly increased PCa cell resistance (instead of sensitivity) to PARP inhibition. CHEK2 plays a role in HR repair and CHEK2 alterations are currently used to predict olaparib response in the FDA-approved HR repair gene panel. The goal of this project is to determine to what extent loss of CHEK2 renders PCa cells resistant to PARP inhibition and define the underlying mechanisms in preclinical PCa models. At completion of this project, we expect to demonstrate that CHEK2 loss is a biomarker to predict PARPi resistance. The findings from this study may change patient eligibility for PARP inhibition and have a positive impact on future clinical practice.