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.
Keywords: DNA repair; Head and neck cancer; Homologous recombination; Poly (ADP-ribose) polymerase; Rucaparib.
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