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

Liu, P. H., Shah, R. B., Li, Y., Arora, A., Ung, P. M., Raman, R., Gorbatenko, A., Kozono, S., Zhou, X. Z., Brechin, V., Barbaro, J. M., Thompson, R., White, R. M., Aguirre-Ghiso, J. A., Heymach, J. V., Lu, K. P., Silva, J. M., Panageas, K. S., Schlessinger, A., Maki, R. G., Skinner, H. D., de Stanchina, E., Sidi, S. (January 2019) An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy. Nat Cell Biol, 21 (2). pp. 203-213. ISSN 1465-7392

URL: https://www.ncbi.nlm.nih.gov/pubmed/30664786
DOI: 10.1038/s41556-018-0260-7

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-kappaB, 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.

Item Type: Paper
Subjects: Investigative techniques and equipment > radiation treatment and equipment
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
organism description > animal > fish > zebrafish
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matthew Dunn
Date: 21 January 2019
Date Deposited: 29 Jan 2019 15:49
Last Modified: 23 Apr 2019 14:43
PMCID: PMC6428421
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37664

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