PUBLICATION
An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy
- Authors
- 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.
- ID
- ZDB-PUB-190122-13
- Date
- 2019
- Source
- Nature cell biology 21(2): 203-213 (Journal)
- Registered Authors
- Liu, Peter H., Sidi, Samuel, Thompson, Ruth, White, Richard M.
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- HCT116 Cells
- HEK293 Cells
- HeLa Cells
- Humans
- Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors
- Interleukin-1 Receptor-Associated Kinases/genetics
- Interleukin-1 Receptor-Associated Kinases/metabolism*
- MCF-7 Cells
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Mutation
- NIMA-Interacting Peptidylprolyl Isomerase/antagonists & inhibitors
- NIMA-Interacting Peptidylprolyl Isomerase/genetics
- NIMA-Interacting Peptidylprolyl Isomerase/metabolism*
- Neoplasms/genetics
- Neoplasms/metabolism
- Neoplasms/radiotherapy*
- Radiation Tolerance/drug effects
- Radiation Tolerance/genetics
- Signal Transduction*
- Tumor Suppressor Protein p53/genetics
- Xenograft Model Antitumor Assays/methods*
- Zebrafish
- PubMed
- 30664786 Full text @ Nat. Cell Biol.
Citation
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. (2019) An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy. Nature cell biology. 21(2):203-213.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping