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

Peter H. Liu, Richa B. Shah, Yuanyuan Li, Arshi Arora, Peter Man Un Ung, Renuka Raman, Andrej Gorbatenko, Shingo Kozono, Xiao Zhen Zhou, Vincent Brechin, John M. Barbaro, Ruth Thompson, Richard M. White, Julio A. Aguirre-Ghiso, John V. Heymach, Kun Ping Lu, Jose M. Silva, Katherine S. Panageas, Avner Schlessinger, Robert G. MakiHeath D. Skinner, Elisa de Stanchina, Samuel Sidi

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)203-213
Number of pages11
JournalNature Cell Biology
Volume21
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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