Targeting the survival kinase DYRK1B: A novel approach to overcome radiotherapy-related treatment resistance

Abstract

BackgroundCancer cell survival under stress conditions is a prerequisite for the development of treatment resistance. The survival kinase DYRK1B is a key regulator of stress survival pathways and might thereby also contribute to radiation resistance. Here we investigate the strategy of targeting DYRK1B in combination with ionizing radiation (IR) to enhance tumor cell killing under stress conditions. MethodsDYRK1B expression, ROS formation and DNA damage were investigated under serum-starvation (0.1% FBS), hypoxia (0.2%, 1% O2) and IR. The combined treatment modality of IR and DYRK1B inhibition was investigated in 2D and in spheroids derived from the colorectal cancer cell line SW620, and in primary patient-derived colorectal carcinoma (CRC) organoids. ResultsExpression of DYRK1B was upregulated under starvation and hypoxia, but not in response to IR. The small molecule DYRK1B inhibitor AZ191 and shRNA-mediated DYRK1B knockdown significantly reduced proliferative activity and clonogenicity of SW620 tumor cells alone and in combination with IR under serum-starved conditions, which correlated with increased ROS levels and DNA damage. Furthermore, AZ191 successfully targeted the hypoxic core of tumor spheroids while IR preferentially targeted normoxic cells in the rim of the spheroids. A combined treatment effect was also observed in CRC-organoids but not in healthy tissue-derived organoids. ConclusionCombined treatment with the DYRK1B inhibitor AZ191 and IR resulted in (supra-) additive tumor cell killing in colorectal tumor cell systems and in primary CRC organoids. Mechanistic investigations support the rational to target the stress-enhanced survival kinase DYRK1B in combination with irradiation to overcome hypoxia- and starvation-induced treatment resistances.