Department of Oncology, Georges-François Leclerc Cancer Center, UNICANCER, F-21079 Dijon, France.
Molecular Biology Unit, Department of Biology and Pathology of Tumors, Georges-François Leclerc Cancer Center, UNICANCER, F-21079 Dijon, France.
Mol Med Rep. 2021 Jan;23(1). doi: 10.3892/mmr.2020.11713. Epub 2020 Nov 25.
Loss‑of‑function BRCA mutations are frequent in high‑grade serous ovarian carcinoma. BRCA1 and ‑2 mutations lead to homologous recombination (HR) deficiency. Poly(ADP‑ribose) polymerases (PARP) are enzymes involved in DNA repair. PARP inhibitors (PARPi) lead to DNA damage accumulation in cells deficient in HR. Olaparib (a PARPi) is currently used for the treatment of high‑grade serous ovarian carcinoma with germline or somatic BRCA mutations; however, numerous patients do not respond or eventually develop resistance to these agents. The TP53 gene encodes the p53 protein, which is often referred to as the 'guardian of the genome'. TP53 mutations at diagnosis are known to promote resistance to chemotherapy. In the present study, four cases of patients with BRCA‑mutated cancer treated with olaparib, who progressed following the PARPi treatment, are reported. Exome analyses were performed on a primary tumor biopsy at diagnosis, then on a progressing metastasis following olaparib treatment. Exome analyses following olaparib treatment identified TP53 mutations, as well as increased frequencies of pre‑existing TP53 mutations compared with the primary tumor. In HCT116 TP53 cells carrying BRCA2 pathogenic mutations, TP53 inactivating mutations were associated with lower sensitivity to olaparib . Thus, inactivating TP53 mutations may be associated to olaparib resistance in the presence of BRCA mutations. In conclusion, the present findings demonstrated resistance to PARPi with TP53 mutations that may be clinically relevant. As TP53 mutations are easily detectable with targeted next‑generation sequencing panels, these may serve as surrogate markers for the onset of PARPi resistance in the context of routine patient management strategies.
BRCA 功能丧失突变在高级别浆液性卵巢癌中很常见。BRCA1 和 BRCA2 突变导致同源重组（HR）缺陷。聚（ADP-核糖）聚合酶（PARP）是参与 DNA 修复的酶。PARP 抑制剂（PARPi）导致 HR 缺陷细胞中 DNA 损伤的积累。奥拉帕利（一种 PARPi）目前用于治疗具有种系或体细胞 BRCA 突变的高级别浆液性卵巢癌；然而，许多患者对这些药物没有反应或最终产生耐药性。TP53 基因编码 p53 蛋白，通常被称为“基因组的守护者”。诊断时的 TP53 突变已知可促进对化疗的耐药性。在本研究中，报道了 4 例接受奥拉帕利治疗的 BRCA 突变癌症患者，这些患者在 PARPi 治疗后进展。在诊断时对原发性肿瘤活检进行外显子组分析，然后在奥拉帕利治疗后进展的转移灶中进行外显子组分析。奥拉帕利治疗后的外显子组分析鉴定出了 TP53 突变，与原发性肿瘤相比，TP53 突变的频率增加。在携带 BRCA2 致病性突变的 HCT116 TP53 细胞中，TP53 失活突变与对奥拉帕利的敏感性降低相关。因此，在存在 BRCA 突变的情况下，TP53 失活突变可能与奥拉帕利耐药相关。总之，本研究结果表明存在 TP53 突变的 PARPi 耐药性可能具有临床相关性。由于靶向下一代测序panel 可以容易地检测到 TP53 突变，因此这些突变可能作为 PARPi 耐药发生的替代标志物，用于常规患者管理策略。
