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Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models
Head and neck squamous cell carcinoma (HNSCC) currently only has one FDA-approved cancer intrinsic targeted therapy, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, to which only approximately 10% of tumors are sensitive. In order to extend therapy options, we subjected patient-deri...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300392/ https://www.ncbi.nlm.nih.gov/pubmed/29856687 http://dx.doi.org/10.1080/15384047.2018.1451285 |
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author | Ouyang, Xiaoming Barling, Ashley Lesch, Aletha Tyner, Jeffrey W. Choonoo, Gabrielle Zheng, Christina Jeng, Sophia West, Toni M. Clayburgh, Daniel Courtneidge, Sara A. McWeeney, Shannon K. Kulesz-Martin, Molly |
author_facet | Ouyang, Xiaoming Barling, Ashley Lesch, Aletha Tyner, Jeffrey W. Choonoo, Gabrielle Zheng, Christina Jeng, Sophia West, Toni M. Clayburgh, Daniel Courtneidge, Sara A. McWeeney, Shannon K. Kulesz-Martin, Molly |
author_sort | Ouyang, Xiaoming |
collection | PubMed |
description | Head and neck squamous cell carcinoma (HNSCC) currently only has one FDA-approved cancer intrinsic targeted therapy, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, to which only approximately 10% of tumors are sensitive. In order to extend therapy options, we subjected patient-derived HNSCC cells to small-molecule inhibitor and siRNA screens, first, to find effective combination therapies with an EGFR inhibitor, and second, to determine a potential mechanistic basis for repurposing the FDA approved agents for HNSCC. The combinations of EGFR inhibitor with anaplastic lymphoma kinase (ALK) inhibitors demonstrated synergy at the highest ratio in our cohort, 4/8 HNSCC patients' derived tumor cells, and this corresponded with an effectiveness of siRNA targeting ALK combined with the EGFR inhibitor gefitinib. Co-targeting EGFR and ALK decreased HNSCC cell number and colony formation ability and increased annexin V staining. Because ALK expression is low and ALK fusions are infrequent in HNSCC, we hypothesized that gefitinib treatment could induce ALK expression. We show that ALK expression was induced in HNSCC patient-derived cells both in 2D and 3D patient-derived cell culture models, and in patient-derived xenografts in mice. Four different ALK inhibitors, including two (ceritinib and brigatinib) FDA approved for lung cancer, were effective in combination with gefitinib. Together, we identified induction of ALK by EGFR inhibitor as a novel mechanism potentially relevant to resistance to EGFR inhibitor, a high ratio of response of HNSCC patient-derived tumor cells to a combination of ALK and EGFR inhibitors, and applicability of repurposing ALK inhibitors to HNSCC that lack ALK aberrations. |
format | Online Article Text |
id | pubmed-6300392 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-63003922018-12-20 Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models Ouyang, Xiaoming Barling, Ashley Lesch, Aletha Tyner, Jeffrey W. Choonoo, Gabrielle Zheng, Christina Jeng, Sophia West, Toni M. Clayburgh, Daniel Courtneidge, Sara A. McWeeney, Shannon K. Kulesz-Martin, Molly Cancer Biol Ther Research Paper Head and neck squamous cell carcinoma (HNSCC) currently only has one FDA-approved cancer intrinsic targeted therapy, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, to which only approximately 10% of tumors are sensitive. In order to extend therapy options, we subjected patient-derived HNSCC cells to small-molecule inhibitor and siRNA screens, first, to find effective combination therapies with an EGFR inhibitor, and second, to determine a potential mechanistic basis for repurposing the FDA approved agents for HNSCC. The combinations of EGFR inhibitor with anaplastic lymphoma kinase (ALK) inhibitors demonstrated synergy at the highest ratio in our cohort, 4/8 HNSCC patients' derived tumor cells, and this corresponded with an effectiveness of siRNA targeting ALK combined with the EGFR inhibitor gefitinib. Co-targeting EGFR and ALK decreased HNSCC cell number and colony formation ability and increased annexin V staining. Because ALK expression is low and ALK fusions are infrequent in HNSCC, we hypothesized that gefitinib treatment could induce ALK expression. We show that ALK expression was induced in HNSCC patient-derived cells both in 2D and 3D patient-derived cell culture models, and in patient-derived xenografts in mice. Four different ALK inhibitors, including two (ceritinib and brigatinib) FDA approved for lung cancer, were effective in combination with gefitinib. Together, we identified induction of ALK by EGFR inhibitor as a novel mechanism potentially relevant to resistance to EGFR inhibitor, a high ratio of response of HNSCC patient-derived tumor cells to a combination of ALK and EGFR inhibitors, and applicability of repurposing ALK inhibitors to HNSCC that lack ALK aberrations. Taylor & Francis 2018-08-17 /pmc/articles/PMC6300392/ /pubmed/29856687 http://dx.doi.org/10.1080/15384047.2018.1451285 Text en © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Research Paper Ouyang, Xiaoming Barling, Ashley Lesch, Aletha Tyner, Jeffrey W. Choonoo, Gabrielle Zheng, Christina Jeng, Sophia West, Toni M. Clayburgh, Daniel Courtneidge, Sara A. McWeeney, Shannon K. Kulesz-Martin, Molly Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models |
title | Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models |
title_full | Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models |
title_fullStr | Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models |
title_full_unstemmed | Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models |
title_short | Induction of anaplastic lymphoma kinase (ALK) as a novel mechanism of EGFR inhibitor resistance in head and neck squamous cell carcinoma patient-derived models |
title_sort | induction of anaplastic lymphoma kinase (alk) as a novel mechanism of egfr inhibitor resistance in head and neck squamous cell carcinoma patient-derived models |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300392/ https://www.ncbi.nlm.nih.gov/pubmed/29856687 http://dx.doi.org/10.1080/15384047.2018.1451285 |
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