Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling
<p><strong>Objectives</strong> 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, radiores...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2019
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| _version_ | 1826289330087264256 |
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| author | Qureishi, A Rieunier, G Shah, K Aleksic, T Winter, S Møller, H Macaulay, V |
| author_facet | Qureishi, A Rieunier, G Shah, K Aleksic, T Winter, S Møller, H Macaulay, V |
| author_sort | Qureishi, A |
| collection | OXFORD |
| description | <p><strong>Objectives</strong> 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.</p> <p><strong>Design</strong> We compared IGF‐1R and EGFR immunohistochemical scores in LSCC patients 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 <em>in vitro</em>, two LSCC cell lines underwent clinically‐relevant irradiation to 55 Gy in 2.75 Gy fractions.</p> <p><strong>Results</strong> IGF‐1R 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. <em>In vitro</em>, 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.</p> <p><strong>Conclusions</strong> Radiation upregulates IGF‐1R and may enhance IGF/EGFR dependence, suggesting that IGF/EGFR blockade may have activity in LSCCs that recur post‐radiotherapy.</p> |
| first_indexed | 2024-03-07T02:27:13Z |
| format | Journal article |
| id | oxford-uuid:a607e373-b6bc-4b0a-b6d0-2588738cd127 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:27:13Z |
| publishDate | 2019 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:a607e373-b6bc-4b0a-b6d0-2588738cd1272022-03-27T02:44:30ZRadioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signallingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a607e373-b6bc-4b0a-b6d0-2588738cd127EnglishSymplectic Elements at OxfordWiley2019Qureishi, ARieunier, GShah, KAleksic, TWinter, SMøller, HMacaulay, V<p><strong>Objectives</strong> 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.</p> <p><strong>Design</strong> We compared IGF‐1R and EGFR immunohistochemical scores in LSCC patients 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 <em>in vitro</em>, two LSCC cell lines underwent clinically‐relevant irradiation to 55 Gy in 2.75 Gy fractions.</p> <p><strong>Results</strong> IGF‐1R 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. <em>In vitro</em>, 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.</p> <p><strong>Conclusions</strong> Radiation upregulates IGF‐1R and may enhance IGF/EGFR dependence, suggesting that IGF/EGFR blockade may have activity in LSCCs that recur post‐radiotherapy.</p> |
| spellingShingle | Qureishi, A Rieunier, G Shah, K Aleksic, T Winter, S Møller, H Macaulay, V Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling |
| title | Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling |
| title_full | Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling |
| title_fullStr | Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling |
| title_full_unstemmed | Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling |
| title_short | Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling |
| title_sort | radioresistant laryngeal cancers upregulate type 1 igf receptor and exhibit increased cellular dependence on igf and egf signalling |
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