Introduction: Recently, a combination of the pro-apoptotic SMAC mimetic xevinapant and radiochemotherapy (RCT) was the first study arm ever to show superiority over RCT alone in HNSCC. The proportion of HPV-pos. patients in this randomized phase 2 trial was only 8% and there are very limited preclinical data on radiosensitization of HPV-pos. HNSCC. Since further clinical trials with xevinapant are currently being initiated that also include HPV-pos. HNSCC we are performing thorough preclinical analyses on the radiosensitization of HPV-pos. HNSCC cells through xevinapant alone, as well as the combination with another promising substance, the ATR-inhibitor tuvusertib.

Materials and Methods: Assessment of sole inhibitor treatment through proliferation and colony formation assays. Assessment of radiosensitization through analysis of colony formation after sole and dual inhibition in combination with X-irradiation. Analysis of apoptosis induction through staining of activated caspase 3 and caspase 3 substrate assay.

Results: Tuvusertib conferred profound radiosensitization in all 5 HPV+ HNSCC cell lines tested so far. Sensitivity towards xevinapant varied with different strains demonstrating either resistance, moderate radiosensitization or high sensitivity already under single treatment. Interestingly, sensitivity and radiosensitization were not always accompanied with caspase 3 activity. Combined treatment was highly toxic in all cell lines tested so far.

Conclusion: Sensitivity of HPV+ HNSCC cells towards xevinapant varies and prospective biomarkers would be desirable. ATR-inhibition results in profound radiosensitization and the combination of both agents appears highly promising. Mechanisms of cell death induction through xevinapant warrants further investigations.

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