Comparative Therapeutic Exploitability of Acute Adaptation Mechanisms to Photon and Proton Irradiation in 3D Head and Neck Squamous Cell Carcinoma Cell Cultures

Simple Summary Treatment resistance is a major obstacle affecting the outcome of patients with head and neck squamous cell carcinomas (HNSCC). Proton beam therapy may be beneficial in the treatment of HNSCC due to optimized dose distribution and consequent sparing of healthy tissue. However, molecular data on tumor cell responses upon proton irradiation appear sparse. The aim of this study was to compare the acute adaptative kinome of HNSCC cell lines to photon and proton irradiation and elucidate their therapeutic potential. Despite pronounced differences in kinome profiles upon photon and proton irradiation, these differences failed to be therapeutically exploitable. Instead, our results reveal radiation type-independent sensitization upon pharmacological inhibition of selected targets. For better tumor control, high-precision proton beam radiation therapy is currently being intensively discussed relative to conventional photon therapy. Here, we assumed that radiation type-specific molecular response profiles in more physiological 3D, matrix-based head and neck squamous cell carcinoma (HNSCC) cell cultures can be identified and therapeutically exploited. While proton irradiation revealed superimposable clonogenic survival and residual DNA double strand breaks (DSB) relative to photon irradiation, kinome profiles showed quantitative differences between both irradiation types. Pharmacological inhibition of a subset of radiation-induced kinases, predominantly belonging to the mitogen-activated protein kinase (MAPK) family, failed to sensitize HNSCC cells to either proton or photon irradiation. Likewise, inhibitors for ATM, DNA-PK and PARP did not discriminate between proton and photon irradiation but generally elicited a radiosensitization. Conclusively, our results suggest marginal cell line-specific differences in the radiosensitivity and DSB repair without a superiority of one radiation type over the other in 3D grown HNSCC cell cultures. Importantly, radiation-induced activity changes of cytoplasmic kinases induced during the first, acute phase of the cellular radiation response could neither be exploited for sensitization of HNSCC cells to photon nor proton irradiation.

Automated summary

Treatment resistance is a major obstacle for HNSCC patients, and proton beam therapy may offer benefits due to optimized dose distribution. However, molecular data on tumor cell responses to proton irradiation are limited. Despite differences in kinome profiles upon photon and proton irradiation, they were not therapeutically exploitable. Pharmacological inhibition of selected targets showed sensitization independent of radiation type. High-precision proton beam therapy is intensively discussed as a potential approach for better tumor control.