p53-dependent treatment response to DNA-PK inhibition in combination with irradiation in head and neck squamous cell carcinoma models

Hayrapetyan, Liana; Roth, Selina Moara; Hovhannisyan, Lusine; Aebersold, Daniel Matthias; Zimmer, Yitzhak; Medova, Michaela (17 January 2023). p53-dependent treatment response to DNA-PK inhibition in combination with irradiation in head and neck squamous cell carcinoma models. Strahlentherapie und Onkologie, p. 211. Springer

Aims: M3814 is a small-molecule inhibitor of DNA-PK, a key regulator of nonhomologous end joining (NHEJ). Inhibition of NHEJ along with irradiation (IR)- induced DNA double-strand breaks can potentially increase antitumor treatment efficacy. This study aims to investigate responses of head and neck squamous cell carcinomas with distinct HPV and p53 status to the treatment with IR, DNA-PK inhibition, and their combination.
Methods: Three groups of cell lines with various HPV/p53 genotypes (p53-wt/HPV–; p53-mutated/HPV–, and p53-wt/HPV+) were treated by M3814, 4 Gy IR, or a combination of M3814 and IR. In addition to viability and cell cycle assays, caspase 3 activity and senescence-associated β-galactosidase assays were used to evaluate cell fates such as apoptosis and senescence. yH2AX and RAD51 foci immunostainings at different time points were implemented to assess the levels of DNA damage and its repair. NMRI- nu mice with subcutaneous xenografts of p53-wt/HPV+ and p53-wt/HPV- cell lines were treated with either
fractionated 10 Gy IR (delivered with the small animal radiation therapy system SmART) alone or in combination with orally distributed M3814.
Results: Decreased number of viable cells after IR alone and particularly after combined
treatment was observed in most of the cell lines. Inhibition of NHEJ combined with IR induces an abrogation of proliferation with different cell fates. Whereas HPV+ and p53-mutated
cells undergo apoptosis due to a common alteration in the p53 pathways, p53-wt cells are preferentially eliminated through senescence. Elevated yH2AX foci formation after 24 and 48 h in the combination treatment group indicates unresolved persistent DNA damage. In vivo, significant effects of IR and of the combination treatment on tumor growth control were observed particularly in p53-wt/HPV+ xenografts.
Conclusion: M3814 radiosensitizes HNSCC tumors and leads to better treatment response in dysfunctional p53 cells. Determination of the HPV and p53 status in a particular tumor might be necessary to effectively shape the intervention outcome when combining NHEJ targeting
with radiation therapy.

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