AbstractObjectivesPatients failing radiotherapy for laryngeal squamous cell carcinoma (LSCC) often require salvage total laryngectomy which has major functional consequences, highlighting a need for biomarkers of radiotherapy resistance. In other tumour types, radioresistance has been linked to epidermal growth factor receptor (EGFR) and type 1 insulin‐like growth factor receptor (IGF‐1R). Here, we evaluated IGF‐1R and EGFR as predictors and mediators of LSCC radioresistance.DesignWe compared IGF‐1R and EGFR immunohistochemical scores in patients with LSCC achieving long‐term remission post‐radiotherapy (n = 23), patients treated with primary laryngectomy (n = 22) or salvage laryngectomy following radiotherapy recurrence (n = 18). To model radioresistance in vitro, two LSCC cell lines underwent clinically relevant irradiation to 55 Gy in 2.75 Gy fractions.ResultsType 1 insulin‐like growth factor receptor expression was higher in pre‐treatment biopsies of radiotherapy failures compared with those in long‐term remission and was upregulated post‐radiotherapy. Patients undergoing primary laryngectomy had more advanced T/N stage and greater tumour IGF‐1R content than those achieving long‐term remission. Pre‐treatment EGFR did not associate with radiotherapy outcomes but showed a trend to upregulation post‐irradiation. In vitro, radiosensitivity was enhanced by inhibition of EGFR but not IGF. Repeated irradiation upregulated IGF‐1R in BICR18 and SQ20B cells and EGFR in SQ20B, and enhanced SQ20B radioresistance. Repeatedly irradiated SQ20B_55 cells were not radiosensitised by inhibition of IGF and/or EGFR, but IGF‐1R:EGFR co‐inhibition suppressed baseline cell survival more effectively than blockade of either pathway alone, and more effectively than in parental cells.ConclusionsRadiation upregulates IGF‐1R and may enhance IGF/EGFR dependence, suggesting that IGF/EGFR blockade may have activity in LSCCs that recur post‐radiotherapy.