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Published on: April 22, 2019
Poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer
Jana Heitmann1, Paul Geeleher2, Zhixiang Zuo2
1Section 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.
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.
Insights
Poly (ADP-ribose) polymerase inhibitors (PARPi) show promise for treating head and neck cancer (HNC) with homologous recombination deficiency (HRD). Rucaparib demonstrated significant activity in a subset of HNC cell lines, suggesting PARPi as a potential HNC therapy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective against tumors with homologous recombination deficiency (HRD), particularly those with BRCA mutations.
- Homologous recombination is a critical DNA repair pathway.
- Head and neck cancer (HNC) treatment landscape requires novel therapeutic strategies.
Purpose of the Study:
- To investigate the potential efficacy of PARPi in head and neck cancer (HNC) by evaluating homologous recombination deficiency (HRD) in HNC tumors.
- To assess the activity of three PARPi (rucaparib, olaparib, veliparib) in a panel of HNC cell lines.
- To explore the relationship between HRD markers and PARPi response in HNC.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) data to identify HRD signatures in HNC.
- Performed cell viability assays to compare PARPi potency in HNC and BRCA-deficient breast cancer cell lines.
- Assessed DNA repair foci (γH2AX, RAD51) via immunofluorescence and analyzed gene expression using microarrays.
Main Results:
- Identified a subset of HNC patients with genomic aberrations indicative of HRD.
- Rucaparib exhibited superior activity compared to olaparib and veliparib, showing single-agent efficacy in a subset of HNC cell lines.
- Significant differences in DNA repair foci formation were observed between rucaparib-sensitive and resistant HNC cells, with chromosome structure gene expression linked to resistance.
Conclusions:
- PARPi are effective in a subset of HNC cell lines, indicating potential therapeutic utility.
- Homologous recombination deficiency (HRD) may be present in head and neck cancer (HNC) in vivo.
- These findings suggest that PARPi could represent a novel treatment option for HNC patients with HRD.
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