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首页> 外文期刊>Oral oncology >Poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer
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Poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer

机译：聚（ADP-核糖）聚合酶抑制剂在头颈癌中的功效

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Objectives Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown single agent activity against tumors with deficiencies in the DNA repair mechanism homologous recombination including, but not limited to those harboring BRCA mutations. We hypothesized that, in the context of homologous recombination deficiency (HRD), PARPi could have an effect in head and neck cancer (HNC). Materials and Methods We evaluated TCGA data for evidence of HRD using a copy number data signature established for breast cancer. The comparative potency of three PARPi was evaluated using cell viability assays in a panel of HNC cell lines and response was compared to BRCA-deficient breast cancer cell lines. The change in foci formation of γH2AX and RAD51 was assessed with immunofluorescent staining after exposure to a PARPi. Baseline gene expression was analyzed using microarray data. Results We found a subgroup in the TCGA HNC cohort harboring genomic aberrations consistent with HRD in breast cancer. Rucaparib activity was superior to olaparib and veliparib and showed single agent activity in a subset of HNC cell lines that was comparable to BRCA-deficient breast cancer cell lines. Rucaparib-sensitive and rucaparib-resistant groups showed significant differences in γH2AX and RAD51 foci formation after rucaparib exposure. Expression of genes involved in chromosome structure was strongly associated with rucaparib resistance. Conclusion We demonstrate that PARPi are effective in a subset of HNC cell lines and propose that HRD may be present in HNC in vivo suggesting that these compounds could play a role in the treatment of HNC.
机译：目的聚（ADP-核糖）聚合酶抑制剂（PARPi）已显示出针对具有DNA修复机制同源重组缺陷的肿瘤的单药活性，包括但不限于具有BRCA突变的那些。我们假设，在同源重组缺陷（HRD）的背景下，PARPi可能对头颈癌（HNC）有影响。材料和方法我们使用为乳腺癌建立的拷贝数数据签名评估了TCGA数据作为HRD的证据。在一组HNC细胞系中使用细胞活力测定法评估了三种PARPi的相对效价，并将其与BRCA缺陷型乳腺癌细胞系进行了比较。暴露于PARPi后，通过免疫荧光染色评估了γH2AX和RAD51灶形成的变化。使用微阵列数据分析基线基因表达。结果我们在TCGA HNC队列中发现了一个亚组，该亚组具有与HRD一致的乳腺癌基因组异常。 Rucaparib活性优于olaparib和veliparib，并且在HNC细胞系的一个子集中显示出与BRCA缺陷型乳腺癌细胞系相当的单药活性。 rucaparib敏感和rucaparib耐药组在rucaparib暴露后显示γH2AX和RAD51灶形成的显着差异。涉及染色体结构的基因表达与rucaparib抗性密切相关。结论我们证明PARPi在一部分HNC细胞系中有效，并提出HRD在体内可能存在于HNC中，提示这些化合物可能在HNC的治疗中发挥作用。

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