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Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution
Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624912/ https://www.ncbi.nlm.nih.gov/pubmed/37923925 http://dx.doi.org/10.1038/s41698-023-00464-y |
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author | Schneider, Jaime L. Shaverdashvili, Khvaramze Mino-Kenudson, Mari Digumarthy, Subba R. Do, Andrew Liu, Audrey Gainor, Justin F. Lennerz, Jochen K. Burns, Timothy F. Lin, Jessica J. |
author_facet | Schneider, Jaime L. Shaverdashvili, Khvaramze Mino-Kenudson, Mari Digumarthy, Subba R. Do, Andrew Liu, Audrey Gainor, Justin F. Lennerz, Jochen K. Burns, Timothy F. Lin, Jessica J. |
author_sort | Schneider, Jaime L. |
collection | PubMed |
description | Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance. |
format | Online Article Text |
id | pubmed-10624912 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106249122023-11-05 Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution Schneider, Jaime L. Shaverdashvili, Khvaramze Mino-Kenudson, Mari Digumarthy, Subba R. Do, Andrew Liu, Audrey Gainor, Justin F. Lennerz, Jochen K. Burns, Timothy F. Lin, Jessica J. NPJ Precis Oncol Case Report Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance. Nature Publishing Group UK 2023-11-03 /pmc/articles/PMC10624912/ /pubmed/37923925 http://dx.doi.org/10.1038/s41698-023-00464-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Case Report Schneider, Jaime L. Shaverdashvili, Khvaramze Mino-Kenudson, Mari Digumarthy, Subba R. Do, Andrew Liu, Audrey Gainor, Justin F. Lennerz, Jochen K. Burns, Timothy F. Lin, Jessica J. Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution |
title | Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution |
title_full | Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution |
title_fullStr | Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution |
title_full_unstemmed | Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution |
title_short | Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution |
title_sort | lorlatinib and capmatinib in a ros1-rearranged nsclc with met-driven resistance: tumor response and evolution |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624912/ https://www.ncbi.nlm.nih.gov/pubmed/37923925 http://dx.doi.org/10.1038/s41698-023-00464-y |
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