Abstract
OBJECTIVES: Patients 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.
DESIGN: We 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.
RESULTS: Type 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.
CONCLUSIONS: Radiation upregulates IGF-1R and may enhance IGF/EGFR dependence, suggesting that IGF/EGFR blockade may have activity in LSCCs that recur post-radiotherapy.
Original language | English |
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Journal | Clinical otolaryngology |
Volume | 44 |
Issue number | 6 |
Pages (from-to) | 1026-1036 |
Number of pages | 11 |
ISSN | 1749-4478 |
DOIs | |
Publication status | Published - Nov 2019 |
Externally published | Yes |
Bibliographical note
© 2019 John Wiley & Sons Ltd.Keywords
- Aged
- Carcinoma, Squamous Cell/metabolism
- Cohort Studies
- Epidermal Growth Factor/metabolism
- Female
- Humans
- Laryngeal Neoplasms/metabolism
- Laryngectomy
- Male
- Middle Aged
- Predictive Value of Tests
- Radiation Tolerance
- Receptor, IGF Type 1/metabolism
- Signal Transduction/physiology
- Somatomedins/metabolism