An IRAK1-PIN1 Signalling Axis Drives Intrinsic Tumour Resistance to Radiation Therapy

Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (e.g., platinums) and a lack of targeted alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic, oxfendazole. Surprisingly, oxfendazole acts via inhibition of IRAK1, a kinase otherwise involved in Interleukin-1 and Toll-like receptor (IL-1R/TLR) immune responses. IRAK1 drives R-RT in a pathway involving IRAK4 and TRAF6 but not the IL-1R/TLR—IRAK adaptor MyD88. Rather than stimulating NF-κB, radiation-activated IRAK1 acts to prevent apoptosis mediated by the PIDDosome complex (PIDD/RAIDD/caspase-2). Countering this pathway with IRAK1 inhibitors suppresses R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Lastly, IRAK1 inhibitors synergize with inhibitors of PIN1, a prolyl isomerase essential for IRAK1 activation in response to pathogens and, as shown here, ionizing radiation. These data identify an IRAK1 radiation-response pathway as a rational chemo-RT target.