Correlation of Homologous Recombination Deficiency in Head and Neck Cancer with Sensitivity to Parp Inhibition

6094 Background: Cancers deficient in homologous recombination (HR) exhibit synthetic lethality when treated with poly (ADP-ribose) polymerase (PARP) inhibitors and may be more sensitive to platinum based therapies. While BRCA1/2 mutations are uncommon in head and neck cancer (HNC), we hypothesized that other mechanisms of HR deficiency occur frequently. Methods: We employed three methods to determine homologous recombination deficiency (HRD): (1) HRD-score, (2) Large-scale chromosomal breaks (Popova et al), (3) BRCA-like CN profile (Schouten et al) using HNC TCGA and Chicago HNC Genomic cohort (CHGC) data. We furthermore screened for HR pathway mutations in both genomic cohorts. Single agent activity of three PARP inhibitors (veliparib (non-locking), olaparib and rucaparib (locking)) was evaluated in a panel of 10 HNC cell lines (colony formation, viability) and compared with a BRCA deficient breast cancer cell line. Immunofluorescent staining for γH2AX and RAD51 was performed. A gene signature of HRD deficiency was developed. Results: HR deficiency was present in 25% of HNC, and was largely concordant between all three methods (1. and 2. had the highest correlation), but were not related to BRCA1/2 mutations in HNC TCGA. BRCA1/2 mutations were rare (<1%) and of unclear significance. In a panel of HNC cell lines rucaparib showed the highest potency as a single agent with three cell lines exhibiting sensitivity (IC50: 7.0µM, 10.3µM and 11.7µM), comparable or superior to a BRCA deficient breast cancer cell line (IC50value: 8.9µM). Seven HNC cell lines were more resistant to single agent PARP inhibition. Foci formation of the HR marker RAD51 did not serve as a reliable biomarker in those cell lines, but our newly developed gene expression signature was applicable. Conclusions: In conclusion, we discover that HR-deficiency is present in 25% of HNC tumors, and benefit of single agent PARP inhibition is present in pre-clinical HNC models, despite the general absence of BRCA mutations in this tumor type. HRD-score is a candidate biomarker to identify patients that may benefit from PARP inhibition, including combinations with cytotoxic chemotherapies or radiation in the future.