Jana Heitmann1, Paul Geeleher2, Zhixiang Zuo3, Ralph R Weichselbaum4, Everett E Vokes5, Sebastian Fetscher6, Tanguy Y Seiwert7. 1. 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. Electronic address: jana@seiwertlab.com. 2. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: paulgeeleher@gmail.com. 3. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: zhixiang@seiwertlab.com. 4. Department of Radiation Oncology, University of Chicago, Chicago, IL 60637, USA; The University of Chicago Comprehensive Cancer Center, Chicago, IL 60627, USA. Electronic address: rrw@radonc.bsd.uchicago.edu. 5. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: evokes@medicine.bsd.uchicago.edu. 6. Division of Hematology and Oncology, Department of Internal Medicine, Sana City Hospital South, Lübeck, Germany. Electronic address: s.fetscher@sana-luebeck.de. 7. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; The University of Chicago Comprehensive Cancer Center, Chicago, IL 60627, USA. Electronic address: tseiwert@medicine.bsd.uchicago.edu.
Abstract
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.
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.
Authors: Damian T Rieke; Sebastian Ochsenreither; Konrad Klinghammer; Tanguy Y Seiwert; Frederick Klauschen; Inge Tinhofer; Ulrich Keilholz Journal: Oncotarget Date: 2016-11-15
Authors: Siva Sai Krishna Dasa; Galina Diakova; Ryo Suzuki; Anne M Mills; Michael F Gutknecht; Alexander L Klibanov; Jill K Slack-Davis; Kimberly A Kelly Journal: Theranostics Date: 2018-04-11 Impact factor: 11.556