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Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors
Purpose: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. The prevalence and characteristics of receptor tyrosine–kinase (RTK) fusion as acquired resistance to EGFR tyrosine–kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively re...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628603/ https://www.ncbi.nlm.nih.gov/pubmed/31372039 http://dx.doi.org/10.2147/CMAR.S197337 |
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author | Xu, Haiyuan Shen, Jinge Xiang, Jianxing Li, Haiyan Li, Bing Zhang, Tengfei Zhang, Lu Mao, Xinru Jian, Hong Shu, Yongqian |
author_facet | Xu, Haiyuan Shen, Jinge Xiang, Jianxing Li, Haiyan Li, Bing Zhang, Tengfei Zhang, Lu Mao, Xinru Jian, Hong Shu, Yongqian |
author_sort | Xu, Haiyuan |
collection | PubMed |
description | Purpose: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. The prevalence and characteristics of receptor tyrosine–kinase (RTK) fusion as acquired resistance to EGFR tyrosine–kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed genomic profiling data of 3873 EGFR (exons 18–21)-mutant lung cancer patients with more than once next-generation sequencing detection. A total of 16 patients who acquired RTK fusions during EGFR-TKI treatment with paired pre- and post-EGFR-TKI samples were identified. Their treatment history was collected. Results: Newly acquired RTK fusions during EGFR-TKI treatment included RET (n=6, 37.5%), ALK (n=5, 31.3%), NTRK1 (n=4, 25.0%), ROS1 (n=1, 6.3%), and FGFR3 (n=1, 6.3%). All RET and EML4–ALK fusions were uncommon variants of KIF5B-RET and E2:A20 (V5), respectively. Interestingly, RET fusion occurred only after osimertinib treatment, and contributed to drug resistance in 50% (6 of 12) of patients treated with osimertinib, indicating that fusions had different prevalence when functioning as resistance mechanisms to EGFR TKIs. Moreover, we found that in all patients developing drug resistance to EGFR TKIs due to fusion emergence (n=16), those that had a treatment history of third-generation EGFR TKIs accounted for 75% (n=12). Conclusion: We have extended the current knowledge of resistance mechanisms to EGFR TKIs in non-small-cell lung cancer. Detection of RTK fusions should be included in genomic profiling panels to uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches, to circumvent tumorigenesis. |
format | Online Article Text |
id | pubmed-6628603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-66286032019-08-01 Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors Xu, Haiyuan Shen, Jinge Xiang, Jianxing Li, Haiyan Li, Bing Zhang, Tengfei Zhang, Lu Mao, Xinru Jian, Hong Shu, Yongqian Cancer Manag Res Original Research Purpose: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. The prevalence and characteristics of receptor tyrosine–kinase (RTK) fusion as acquired resistance to EGFR tyrosine–kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed genomic profiling data of 3873 EGFR (exons 18–21)-mutant lung cancer patients with more than once next-generation sequencing detection. A total of 16 patients who acquired RTK fusions during EGFR-TKI treatment with paired pre- and post-EGFR-TKI samples were identified. Their treatment history was collected. Results: Newly acquired RTK fusions during EGFR-TKI treatment included RET (n=6, 37.5%), ALK (n=5, 31.3%), NTRK1 (n=4, 25.0%), ROS1 (n=1, 6.3%), and FGFR3 (n=1, 6.3%). All RET and EML4–ALK fusions were uncommon variants of KIF5B-RET and E2:A20 (V5), respectively. Interestingly, RET fusion occurred only after osimertinib treatment, and contributed to drug resistance in 50% (6 of 12) of patients treated with osimertinib, indicating that fusions had different prevalence when functioning as resistance mechanisms to EGFR TKIs. Moreover, we found that in all patients developing drug resistance to EGFR TKIs due to fusion emergence (n=16), those that had a treatment history of third-generation EGFR TKIs accounted for 75% (n=12). Conclusion: We have extended the current knowledge of resistance mechanisms to EGFR TKIs in non-small-cell lung cancer. Detection of RTK fusions should be included in genomic profiling panels to uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches, to circumvent tumorigenesis. Dove 2019-07-09 /pmc/articles/PMC6628603/ /pubmed/31372039 http://dx.doi.org/10.2147/CMAR.S197337 Text en © 2019 Xu et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Xu, Haiyuan Shen, Jinge Xiang, Jianxing Li, Haiyan Li, Bing Zhang, Tengfei Zhang, Lu Mao, Xinru Jian, Hong Shu, Yongqian Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors |
title |
Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors |
title_full |
Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors |
title_fullStr |
Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors |
title_full_unstemmed |
Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors |
title_short |
Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors |
title_sort | characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to egfr tyrosine–kinase inhibitors |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628603/ https://www.ncbi.nlm.nih.gov/pubmed/31372039 http://dx.doi.org/10.2147/CMAR.S197337 |
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