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

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy Research

Background:

• Drug-based strategies to overcome tumor resistance to radiotherapy (R-RT) are limited by toxicity and lack of targeted options.
• Traditional radiosensitizers often exhibit single-agent toxicity, necessitating novel approaches.
• Identifying compounds that restore radiosensitivity in specific cancer contexts is crucial.

Purpose of the Study:

• To identify novel compounds that restore radiosensitivity in p53 mutant zebrafish.
• To elucidate the mechanism of action for identified radiosensitizing compounds.
• To explore the potential of targeting the identified pathway for chemoradiation therapy.

Main Methods:

• Conducted a screen for compounds restoring radiosensitivity in p53 mutant zebrafish.
• Investigated the mechanism of action of oxfendazole, identifying IRAK1 inhibition.
• Analyzed the IRAK1-dependent pathway involving IRAK4 and TRAF6, independent of MyD88.
• Examined the role of radiation-activated IRAK1 in preventing PIDDosome-mediated apoptosis.
• Tested IRAK1 inhibitors in tumor models and assessed synergy with PIN1 inhibitors.

Main Results:

• Oxfendazole was identified as a compound that restores radiosensitivity.
• Oxfendazole inhibits IRAK1, a kinase previously implicated in immune responses.
• The identified pathway involves IRAK1, IRAK4, and TRAF6, suppressing apoptosis.
• IRAK1 inhibition suppressed R-RT in TP53-mutated cancer models.
• IRAK1 inhibitors synergized with PIN1 inhibitors, highlighting a combined therapeutic strategy.

Conclusions:

• Oxfendazole targets IRAK1 to overcome tumor resistance to radiotherapy.
• The IRAK1-dependent pathway represents a novel target for chemoradiation therapy.
• Targeting IRAK1, particularly in conjunction with PIN1 inhibition, shows promise for treating R-RT in TP53-mutated cancers.