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

Abstract

Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (e.g., 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 inhibition of IRAK1, a kinase otherwise involved in Interleukin-1 and Toll-like receptor (IL-1R/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 NF-κB, radiation-activated IRAK1 acts to prevent apoptosis mediated by the PIDDosome complex (PIDD/RAIDD/caspase-2). Countering this pathway with IRAK1 inhibitors suppresses R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Lastly, IRAK1 inhibitors synergize 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 chemo-RT target.

IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

“…However, the multi-PRR-induced IRAK1 SMOC does not include components of the myddosome and its formation seems to be insensitive to the levels of MyD88 dimerization. In zebrafish, IRAK1 has been shown to regulate a PIDDosome SMOC that drives tumor resistance to radiation therapy independent of MyD88, thereby linking the DNA damage response pathway with TLR signaling (Liu et al, 2019 SMOC formation begins to occur within 30 min of ligand activation, it is less likely that cytosolic PRRs and ligand-induced transcriptional events are involved in its initiation.…”

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growthin vivo

“…We next assessed whether pharmacological inhibition of Pin1 by Sulfopin could recapitulate two previously reported phenotypes associated with Pin1 genetic knockout. First, Pin1 knockout was reported to abrogate phosphorylation of IRAK1 Thr209 and resensitize radioresistant cancer cells to irradiation 31 . Accordingly, we found that treating radioresistant HeLa cells with Sulfopin significantly resensitized them to irradiation in a dose dependent manner (…”

“…AlamarBlue-based cell viability assays were performed as previously described 31 The next day, treat with DMSO, Sulfopin (1 μM), or Sulfopin-AcA (1 μM). Every 3 days, carefully aspirate off the media, add 500 μL of fresh media and retreat.…”

“…Furthermore, Pin1-null mice are resistant to tumorigenesis induced by mutant p53 26 , activated HER2/RAS 27 , or constitutively expressed c-Myc 28 . In addition, Pin1 inhibition sensitizes cancer cells to chemotherapeutics 25,29,30 , radiation therapy 31 and blocks the tumorigenesis of cancer stem cells 16,32,33 . However, as evidenced by the Cancer Dependency Map 34 , Pin1 is not essential to cellular viability and Pin1-null mice are viable, though they develop premature aging phenotypes 7,35 .…”

Targeting the Innate Immune Kinase IRAK1 in Radioresistant Cancer: Double-Edged Sword or One-Two Punch?

“…TLR/IL-1R-independent roles for IRAK1 might explain this paradox, yet until recently no such non-immune IRAK1 function had been reported in vertebrates. In a screen for small molecules that restore RT-induced cell death in otherwise radioresistant p53 mutant zebrafish (47, 48), we identified the microtubule inhibitor, oxfendazole (47). Surprisingly, target discovery identified IRAK1, and not tubulin, as the key target whose inhibition by oxfendazole was responsible for cell death recovery in irradiated fish (47).…”