@article{399542ae77ee4afda131a7e1ddc0caf1,
title = "An IRAK1–PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy",
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, in response to ionizing radiation. These data identify an IRAK1 radiation-response pathway as a rational chemoradiation therapy target.",
author = "Liu, {Peter H.} and Shah, {Richa B.} and Yuanyuan Li and Arshi Arora and Ung, {Peter Man Un} and Renuka Raman and Andrej Gorbatenko and Shingo Kozono and Zhou, {Xiao Zhen} and Vincent Brechin and Barbaro, {John M.} and Ruth Thompson and White, {Richard M.} and Aguirre-Ghiso, {Julio A.} and Heymach, {John V.} and Lu, {Kun Ping} and Silva, {Jose M.} and Panageas, {Katherine S.} and Avner Schlessinger and Maki, {Robert G.} and Skinner, {Heath D.} and {de Stanchina}, Elisa and Samuel Sidi",
note = "Funding Information: The authors thank E. Farias, R. Cagan, A. Dar, R. Krauss, J. Ashwell, X. Li, M. Posner, P. Reddy, R. De Vita and R. Sanchez for helpful comments, technical advice and reagents, and C. Franco and D. Dominguez for zebrafish care. This work was supported in part by the following bodies: NIH/NCI (F30CA186448 to P.H.L.; P30 CA008748 to K.S.P.; RO1CA168485 to H.D.S. and J.V.H; and RO1CA178162 to S.S.); the National Cancer Center NCC CCP (postdoctoral fellowship (to Y.L.); and the JJR Foundation, the Pershing Square Sohn Cancer Research Alliance, the New York Community Trust and the Searle Scholars Program (to S.S.). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = feb,
day = "1",
doi = "10.1038/s41556-018-0260-7",
language = "English",
volume = "21",
pages = "203--213",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "2",
}