Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.
EBioMedicine. 2020 Sep;59:102923. doi: 10.1016/j.ebiom.2020.102923. Epub 2020 Aug 13.
PARP inhibitors are active in various tumour types beyond BRCA-mutant cancers, but their activity and molecular correlates in colorectal cancer (CRC) are not well studied.
Mutations and genome-wide mutational patterns associated with homologous recombination deficiency (HRD) were investigated in 255 primary CRCs with whole-exome sequencing and/or DNA copy number data. Efficacy of five PARP inhibitors and their molecular correlates were evaluated in 93 CRC cell lines partly annotated with mutational-, DNA copy number-, and/or gene expression profiles. Post-treatment gene expression profiling and specific protein expression analyses were performed in two pairs of PARP inhibitor sensitive and resistant cell lines.
A subset of microsatellite stable (MSS) CRCs had truncating mutations in homologous recombination-related genes, but these were not associated with genomic signatures of HRD. Eight CRC cell lines (9%) were sensitive to PARP inhibition, but sensitivity was not predicted by HRD-related genomic and transcriptomic signatures. In contrast, drug sensitivity in MSS cell lines was strongly associated with TP53 wild-type status (odds ratio 15.7, p = 0.023) and TP53-related expression signatures. Increased downstream TP53 activity was among the primary response mechanisms, and TP53 inhibition antagonized the effect of PARP inhibitors. Wild-type TP53-mediated suppression of RAD51 was identified as a possible mechanism of action for sensitivity to PARP inhibition.
PARP inhibitors are active in a subset of CRC cell lines and preserved TP53 function may increase the likelihood of response.
PARP 抑制剂在 BRCA 突变型癌症以外的多种肿瘤类型中具有活性，但它们在结直肠癌（CRC）中的活性和分子相关性尚未得到充分研究。
通过全外显子组测序和/或 DNA 拷贝数数据对 255 例原发性 CRC 进行了与同源重组缺陷（HRD）相关的突变和全基因组突变模式研究。在部分注释了突变、DNA 拷贝数和/或基因表达谱的 93 个 CRC 细胞系中评估了五种 PARP 抑制剂及其分子相关性的疗效。在两对 PARP 抑制剂敏感和耐药细胞系中进行了治疗后基因表达谱分析和特定蛋白质表达分析。
一部分微卫星稳定（MSS）CRC 具有同源重组相关基因的截断突变，但这些突变与 HRD 的基因组特征无关。有 8 个 CRC 细胞系（9%）对 PARP 抑制敏感，但敏感性不能通过 HRD 相关的基因组和转录组特征来预测。相比之下，MSS 细胞系的药物敏感性与 TP53 野生型状态密切相关（优势比 15.7，p=0.023）和与 TP53 相关的表达特征。下游 TP53 活性增加是主要的反应机制之一，TP53 抑制拮抗了 PARP 抑制剂的作用。野生型 TP53 介导的 RAD51 抑制被确定为对 PARP 抑制剂敏感性的可能作用机制。
PARP 抑制剂在一部分 CRC 细胞系中具有活性，保留 TP53 功能可能增加反应的可能性。
