MMS22L loss and PARP inhibition in prostate cancer

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34，500人死亡。mCRPC的治疗选择有限 患者可以延长生命。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（DDR）的基因是最常见的遗传事件之一， mCRPC。这些改变与前列腺癌的特殊治疗脆弱性相关 (PCa)细胞具体地说，同源重组修复（HRR）中的缺陷将预测对 抑制聚（ADP-核糖）聚合酶（PARP）。PARP抑制剂（PARPis）是一种新型的靶向药物， 这种疗法通过阻止PARP酶修复肿瘤细胞中受损的DNA来发挥作用。BRCA1/2 编码HRR所必需的蛋白质。缺乏BRCA 1/2的癌细胞依赖于PARP调节的DNA 对PARPis过敏。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HRR突变（或有害BRCA 1/2突变）的mCRPC患者， 最近临床试验的结果。 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。BRCA 1/2突变可以预测PARPi反应，准确率为50-60%。 然而，具有非BCRA 1/2基因组改变的患者对PARPis的反应程度仍然是未知的。 不清楚通过全基因组CRISPR筛选，我们最近发现PCa中MMS 22 L的缺失 细胞预测对PARP抑制的反应。MMS 22 L是复制叉相关DNA的HRR所必需的 双链断裂。更重要的是，MMS 22 L基因在前列腺肿瘤中经常缺失（约14%）。在 此外，我们的CRISPR筛选结果进一步表明，TP 53或RB 1的缺失可能使PCa 由于HRR基因表达的上调，细胞对PARP的抗性可以通过联合 ATR抑制。因此，本项目的目标是确定（1）MMS 22 L的损失在多大程度上会导致 在临床前PCa模型中对PARP抑制的细胞反应;（2）TP 53或RB 1的失活程度 影响PARPi反应;（3）ATR抑制在多大程度上使耐药PCa细胞对PARP重新敏感 抑制作用该项目的成功完成将为mCRPC患者的未来临床试验奠定基础 MMS 22 L和TP 53/RB 1变异，并显著扩大了PARP合格患者的样本库 抑制作用

ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease that is expected to account for ~ 34,500 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 (DDR) 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 repair (HRR) 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. BRCA1/2 encode proteins essential for HRR. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are hypersensitive to PARPis. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for treatment of mCRPC patients with HRR mutations (or deleterious BRCA1/2 mutations) based on the results from recent clinical trials. One of the major barriers to effective treatment using PARPis is how to select patients who most likely benefit from PARP inhibition. BRCA1/2 mutations can predict PARPi response with 50-60% accuracy. However, the degree to which patients with non-BCRA1/2 genomic alterations respond to PARPis remains unclear. Through genome-wide CRISPR screening, we have recently discovered that loss of MMS22L in PCa cells predicts the response to PARP inhibition. MMS22L is required for HRR of replication fork-associated DNA double strand breaks. More importantly, the MMS22L gene is frequently deleted (~14%) in prostate tumors. In addition, the results from our CRISPR screening further suggest that loss of TP53 or RB1 may render PCa cells resistance to PARPis due to upregulation of HRR gene expression, which can be overcome by combining ATR inhibition. Therefore, the goal of this project is to determine (1) to what extent loss of MMS22L confers a cellular response to PARP inhibition in preclinical PCa models; (2) to what extent inactivation of TP53 or RB1 influences PARPi response; (3) to what extent ATR inhibition re-sensitizes resistant PCa cells to PARP inhibition. The successful completion of this project will set the stage for future clinical trials in mCRPC patients with MMS22L and TP53/RB1 alterations and significantly expand the pool of eligible patients for PARP inhibition.