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
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: |
bioinformatics
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
Investigative techniques and equipment
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
Investigative techniques and equipment > radiation treatment and equipment
organism description > animal
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organism description > animal > mammal > rodent
organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction
organs, tissues, organelles, cell types and functions > tissues types and functions
organism description > animal > fish > zebrafish |
| CSHL Authors: |
|
| Communities: |
CSHL labs > Maki lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: |
Matthew Dunn
|
| Date: |
21 January 2019 |
| Date Deposited: |
29 Jan 2019 15:49 |
| Last Modified: |
02 Feb 2024 17:04 |
| PMCID: |
PMC6428421 |
| Related URLs: |
|
| URI: |
https://repository.cshl.edu/id/eprint/37664 |
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