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An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy

Authors: 
Liu PH, Shah RB, Li Y, Arora A, Ung PM, Raman R, Gorbatenko A, Kozono S, Zhou XZ, Brechin V, Barbaro JM, Thompson R, White RM, Aguirre-Ghiso JA, Heymach JV, Lu KP, Silva JM, Panageas KS, Schlessinger A, Maki RG, Skinner HD, de Stanchina E, Sidi S
Citation: 
Nat Cell Biol. 2019 Jan 21. doi: 10.1038/s41556-018-0260-7. [Epub ahead of print]
Abstract: 
Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, 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 the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (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 nuclear factor-κB, radiation-activated IRAK1 prevented apoptosis mediated by the PIDDosome complex (comprising PIDD, RAIDD and caspase-2). Countering this pathway with IRAK1 inhibitors suppressed R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Moreover, IRAK1 inhibitors synergized 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 chemoradiation therapy target.
Epub: 
Yes
Organism or Cell Type: 
zebrafish
Delivery Method: 
microinjection