Srinivasan Gayathri, Sidhu Gurjit Singh, Williamson Elizabeth A, Jaiswal Aruna S, Najmunnisa Nasreen, Wilcoxen Keith, Jones Dennie, George Thomas J, Hromas Robert
Department of Medicine and the Cancer Center, University of Florida Health, 1600 SW Archer Rd, Gainesville, FL, 32610, USA.
Tesaro, Waltham, MA, 02451, USA.
Cancer Chemother Pharmacol. 2017 Oct;80(4):861-867. doi: 10.1007/s00280-017-3401-y. Epub 2017 Jul 29.
Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.
恶性胸膜间皮瘤(MPM)通常无法通过手术切除,并且对当前的化疗和放疗反应不佳。23%至64%的恶性胸膜间皮瘤在BAP1基因中存在体细胞失活突变。BAP1是一种在BRCA1/BARD1复合物中发现的同源重组(HR)DNA修复成分。与BRCA1/2缺陷型癌症相似,BAP1基因突变会导致HR途径缺陷,并增加对其他DNA修复途径的依赖。我们假设BAP1突变型MPM与BRCA1/2突变型乳腺癌和卵巢癌一样,需要PARP1来维持生存。因此,我们使用临床PARP1抑制剂尼拉帕利和奥拉帕利来评估它们是否能在MPM中诱导合成致死。令人惊讶的是,我们发现所有检测的MPM细胞系,无论BAP1状态如何,都依赖PARP1介导的DNA修复来维持生存。我们发现,无论有无BAP1突变,尼拉帕利和奥拉帕利处理都显著降低了多个MPM细胞系的克隆存活率。这种克隆性细胞死亡可能是由于PARP1抑制在MPM细胞中诱导的广泛复制叉崩溃和基因组不稳定所致。MPM细胞对PARP1的需求表明它们通常可能源于HR DNA修复缺陷。更重要的是,这些数据表明PARP1抑制剂可能对MPM治疗有效,而目前MPM几乎没有有效的治疗方法。