CHEK2 loss promotes prostate cancer resistance to PARP inhibitors

摘要 转移性去势抵抗前列腺癌(MCRPC)是一种无法治愈的疾病，预计 在美国，每年约有33,000人死亡。治疗选择是有限的 延长生命的MCRPC患者。迫切需要开发新的靶向疗法，特别是 基于肿瘤基因组改变的个性化治疗。最近的基因组研究揭示了 具有潜在基因组改变的各种可操作的分子靶点。值得注意的是，基因的改变 参与DNA损伤反应是最常见的遗传事件之一，并富含mCRPC。 这些变化与前列腺癌(PCA)细胞的治疗脆弱性有关。 具体地说，同源重组(HR)修复中的缺陷将预测对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，有效 通过阻止PARP酶修复肿瘤细胞中受损的DNA。BRCA1和BRCA2基因 编码HR修复所必需的蛋白质。缺乏BRCA1/2的癌细胞依赖于PARP调节 DNA修复，对PARPis高度敏感。美国FDA批准了两种PARP抑制剂(奥拉帕利和 Rucaparib)用于治疗具有恶性BRCA1/2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 受益于PARP抑制。对PARPis的耐药性也是一个令人敬畏的临床问题。穿过 全基因组CRISPR(规律性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抵抗PARP抑制的基因。出乎意料的是， 我们发现细胞周期检查点调节因子和肿瘤抑制因子CHEK2(Checkpoint Kinase2)的缺失 该基因显著增加了PCa细胞对PARP抑制的抗性(而不是敏感性)。CHEK2扮演着一个角色 在HR中，修复和CHEK2改变目前用于预测FDA批准的HR对奥拉帕利的反应 修复基因面板。这个项目的目标是确定CHEK2的丢失在多大程度上导致PCA细胞 抵抗PARP抑制，并确定临床前PCA模型的潜在机制。在完成时 在这个项目中，我们希望证明CHEK2缺失是预测PARPI耐药性的一个生物标志物。这个 这项研究的发现可能会改变患者接受PARP抑制的资格，并对未来产生积极影响 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.