Heitmann Jana, Geeleher Paul, Zuo Zhixiang, Weichselbaum Ralph R, Vokes Everett E, Fetscher Sebastian, Seiwert Tanguy Y
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Division of Hematology and Oncology, Department of Internal Medicine, Sana City Hospital South, Lübeck, Germany.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Oral Oncol. 2014 Sep;50(9):825-31. doi: 10.1016/j.oraloncology.2014.06.004. Epub 2014 Jul 10.
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).
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.
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.
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.
聚（ADP - 核糖）聚合酶抑制剂（PARPi）已显示出对DNA修复机制同源重组存在缺陷的肿瘤具有单药活性，包括但不限于携带BRCA突变的肿瘤。我们假设，在同源重组缺陷（HRD）的背景下，PARPi可能对头颈部癌（HNC）有作用。
我们使用为乳腺癌建立的拷贝数数据特征评估了TCGA数据中HRD的证据。在一组HNC细胞系中使用细胞活力测定评估了三种PARPi的相对效力，并将反应与BRCA缺陷的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γH2AX和RAD51灶形成的变化。使用微阵列数据分析基线基因表达。
我们在TCGA HNC队列中发现了一个亚组，其基因组畸变与乳腺癌中的HRD一致。鲁卡帕尼的活性优于奥拉帕尼和维利帕尼，并在一部分HNC细胞系中显示出单药活性，这与BRCA缺陷的乳腺癌细胞系相当。鲁卡帕尼敏感组和鲁卡帕尼耐药组在暴露于鲁卡帕尼后γH2AX和RAD51灶形成方面存在显著差异。参与染色体结构的基因表达与鲁卡帕尼耐药性密切相关。
我们证明PARPi在一部分HNC细胞系中有效，并提出HRD可能在体内HNC中存在提示这些化合物可能在HNC治疗中发挥作用。
