ZFIN ID: ZDB-PUB-190122-13
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.
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.
FIGURES
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.
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