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

• Published in: Nature cell biology Vol. 21; no. 2; pp. 203 - 213
• Main Authors: Liu, Peter H., Shah, Richa B., Li, Yuanyuan, Arora, Arshi, Ung, Peter Man-Un, Raman, Renuka, Gorbatenko, Andrej, Kozono, Shingo, Zhou, Xiao Zhen, Brechin, Vincent, Barbaro, John M., Thompson, Ruth, White, Richard M., Aguirre-Ghiso, Julio A., Heymach, John V., Lu, Kun Ping, Silva, Jose M., Panageas, Katherine S., Schlessinger, Avner, Maki, Robert G., Skinner, Heath D., de Stanchina, Elisa, Sidi, Samuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 13/106; 13/2; 13/89; 14; 14/1; 14/19; 42/41; 59; 631/67; 631/67/1059/485; 631/67/1059/602; 631/80/86/2366; 64; 64/116; 64/60; 82; 96; 96/109; 96/95; Animals; Anthelmintic agents; Antiparasitic agents; Apoptosis; Benzimidazoles; Biomedical and Life Sciences; Cancer; Cancer Research; Cancer treatment; Caspase; Caspase-2; Cell Biology; Cell Line, Tumor; Chemoradiotherapy; Cytokine receptors; Developmental Biology; Genetic aspects; HCT116 Cells; Health aspects; HEK293 Cells; HeLa Cells; Humans; Immune response; Immune system; Inhibitors; Interleukin 1; Interleukin 1 receptors; Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; Interleukins; Ionizing radiation; IRAK protein; Life Sciences; MCF-7 Cells; Medical schools; Methods; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mutation; MyD88 protein; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - radiotherapy; NIMA-Interacting Peptidylprolyl Isomerase - antagonists & inhibitors; NIMA-Interacting Peptidylprolyl Isomerase - genetics; NIMA-Interacting Peptidylprolyl Isomerase - metabolism; Oxfendazole; p53 Protein; Pathogenic microorganisms; Patient outcomes; Peptidylprolyl isomerase; Pin1 protein; Proteins; Radiation (Physics); Radiation therapy; Radiation tolerance; Radiation Tolerance - drug effects; Radiation Tolerance - genetics; Radiosensitivity; Radiosensitizers; Radiotherapy; Signal Transduction; Stem Cells; Synergistic effect; Toll-like receptors; Toxicity; TRAF6 protein; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumors; Xenograft Model Antitumor Assays - methods; Zebrafish
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0260-7

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. Performing a small-molecule screen, Liu et al. identify IRAK as a regulator of PIDDosome activity and tumour radioresistance, and demonstrate a synergistic effect of targeting IRAK1 and PIN1 in response to ionizing radiation.