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RET fusions observed in lung and colorectal cancers are sensitive to ponatinib
Genomic studies are revolutionizing clinical oncology, but bridging the lab and the bedside requires the ability to efficiently interrogate rare genetic lesions in unexpected pathological settings using preclinical models. Oncogenes can exhibit intrinsic drug resistance to targeted therapy in differ...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049858/ https://www.ncbi.nlm.nih.gov/pubmed/30038711 http://dx.doi.org/10.18632/oncotarget.25664 |
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author | Gozgit, Joseph M. Chen, Tzu-Hsiu Song, Youngchul Wardwell, Scott Wang, Frank Cai, Jie Li, Henry Edgren, Henrik Rivera, Victor M. Pritchard, Justin |
author_facet | Gozgit, Joseph M. Chen, Tzu-Hsiu Song, Youngchul Wardwell, Scott Wang, Frank Cai, Jie Li, Henry Edgren, Henrik Rivera, Victor M. Pritchard, Justin |
author_sort | Gozgit, Joseph M. |
collection | PubMed |
description | Genomic studies are revolutionizing clinical oncology, but bridging the lab and the bedside requires the ability to efficiently interrogate rare genetic lesions in unexpected pathological settings using preclinical models. Oncogenes can exhibit intrinsic drug resistance to targeted therapy in different cells of origin, adding complexity to clinical interpretations of genomic findings. Here, we capitalize on the flexibility of engineered cell systems to rapidly profile known multi-kinase inhibitors that harbor rearranged during transfection (RET) kinase activity across multiple RET fusions. Identifying ponatinib as the most potent RET inhibitor tested, we used ponatinib to gauge therapeutic responsiveness in RET fusion-positive patient-derived xenograft (PDX) models. Using a genomics guided outlier approach, we identified 4 RET fusion PDX models with 3 different fusion partners (KIF5B, CCDC6, and NCOA4) in both non-small cell lung cancer and colorectal cancer. By comparing ponatinib activity in RET fusion-positive and RET fusion-negative PDX models alongside a standard of care chemotherapeutic agent, we show that RET fusions in colorectal tumors are therapeutically responsive to RET inhibition. Finally, we suggest that coupling engineered cell systems and genomics guided PDX model selection provides a rapid workflow to triage rare genomics findings. |
format | Online Article Text |
id | pubmed-6049858 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-60498582018-07-23 RET fusions observed in lung and colorectal cancers are sensitive to ponatinib Gozgit, Joseph M. Chen, Tzu-Hsiu Song, Youngchul Wardwell, Scott Wang, Frank Cai, Jie Li, Henry Edgren, Henrik Rivera, Victor M. Pritchard, Justin Oncotarget Research Paper Genomic studies are revolutionizing clinical oncology, but bridging the lab and the bedside requires the ability to efficiently interrogate rare genetic lesions in unexpected pathological settings using preclinical models. Oncogenes can exhibit intrinsic drug resistance to targeted therapy in different cells of origin, adding complexity to clinical interpretations of genomic findings. Here, we capitalize on the flexibility of engineered cell systems to rapidly profile known multi-kinase inhibitors that harbor rearranged during transfection (RET) kinase activity across multiple RET fusions. Identifying ponatinib as the most potent RET inhibitor tested, we used ponatinib to gauge therapeutic responsiveness in RET fusion-positive patient-derived xenograft (PDX) models. Using a genomics guided outlier approach, we identified 4 RET fusion PDX models with 3 different fusion partners (KIF5B, CCDC6, and NCOA4) in both non-small cell lung cancer and colorectal cancer. By comparing ponatinib activity in RET fusion-positive and RET fusion-negative PDX models alongside a standard of care chemotherapeutic agent, we show that RET fusions in colorectal tumors are therapeutically responsive to RET inhibition. Finally, we suggest that coupling engineered cell systems and genomics guided PDX model selection provides a rapid workflow to triage rare genomics findings. Impact Journals LLC 2018-07-03 /pmc/articles/PMC6049858/ /pubmed/30038711 http://dx.doi.org/10.18632/oncotarget.25664 Text en Copyright: © 2018 Gozgit et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Gozgit, Joseph M. Chen, Tzu-Hsiu Song, Youngchul Wardwell, Scott Wang, Frank Cai, Jie Li, Henry Edgren, Henrik Rivera, Victor M. Pritchard, Justin RET fusions observed in lung and colorectal cancers are sensitive to ponatinib |
title | RET fusions observed in lung and colorectal cancers are sensitive to ponatinib |
title_full | RET fusions observed in lung and colorectal cancers are sensitive to ponatinib |
title_fullStr | RET fusions observed in lung and colorectal cancers are sensitive to ponatinib |
title_full_unstemmed | RET fusions observed in lung and colorectal cancers are sensitive to ponatinib |
title_short | RET fusions observed in lung and colorectal cancers are sensitive to ponatinib |
title_sort | ret fusions observed in lung and colorectal cancers are sensitive to ponatinib |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049858/ https://www.ncbi.nlm.nih.gov/pubmed/30038711 http://dx.doi.org/10.18632/oncotarget.25664 |
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