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Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types

Paclitaxel, the most commonly used form of chemotherapy, is utilized in curative protocols in different types of cancer. The response to treatment differs among patients. Biological interpretation of a mechanism to explain this personalized response is still unavailable. Since paclitaxel is known to...

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Autores principales: Ben-Hamo, Rotem, Zilberberg, Alona, Cohen, Helit, Bahar-Shany, Keren, Wachtel, Chaim, Korach, Jacob, Aviel-Ronen, Sarit, Barshack, Iris, Barash, Danny, Levanon, Keren, Efroni, Sol
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478919/
https://www.ncbi.nlm.nih.gov/pubmed/31044156
http://dx.doi.org/10.1038/s41698-019-0084-3
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author Ben-Hamo, Rotem
Zilberberg, Alona
Cohen, Helit
Bahar-Shany, Keren
Wachtel, Chaim
Korach, Jacob
Aviel-Ronen, Sarit
Barshack, Iris
Barash, Danny
Levanon, Keren
Efroni, Sol
author_facet Ben-Hamo, Rotem
Zilberberg, Alona
Cohen, Helit
Bahar-Shany, Keren
Wachtel, Chaim
Korach, Jacob
Aviel-Ronen, Sarit
Barshack, Iris
Barash, Danny
Levanon, Keren
Efroni, Sol
author_sort Ben-Hamo, Rotem
collection PubMed
description Paclitaxel, the most commonly used form of chemotherapy, is utilized in curative protocols in different types of cancer. The response to treatment differs among patients. Biological interpretation of a mechanism to explain this personalized response is still unavailable. Since paclitaxel is known to target BCL2 and TUBB1, we used pan-cancer genomic data from hundreds of patients to show that a single-nucleotide variant in the BCL2 sequence can predict a patient’s response to paclitaxel. Here, we show a connection between this BCL2 genomic variant, its transcript structure, and protein abundance. We demonstrate these findings in silico, in vitro, in formalin-fixed paraffin-embedded (FFPE) tissue, and in patient lymphocytes. We show that tumors with the specific variant are more resistant to paclitaxel. We also show that tumor and normal cells with the variant express higher levels of BCL2 protein, a phenomenon that we validated in an independent cohort of patients. Our results indicate BCL2 sequence variations as determinants of chemotherapy resistance. The knowledge of individual BCL2 genomic sequences prior to the choice of chemotherapy may improve patient survival. The current work also demonstrates the benefit of community-wide, integrative omics data sources combined with in-lab experimentation and validation sets.
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spelling pubmed-64789192019-05-01 Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types Ben-Hamo, Rotem Zilberberg, Alona Cohen, Helit Bahar-Shany, Keren Wachtel, Chaim Korach, Jacob Aviel-Ronen, Sarit Barshack, Iris Barash, Danny Levanon, Keren Efroni, Sol NPJ Precis Oncol Article Paclitaxel, the most commonly used form of chemotherapy, is utilized in curative protocols in different types of cancer. The response to treatment differs among patients. Biological interpretation of a mechanism to explain this personalized response is still unavailable. Since paclitaxel is known to target BCL2 and TUBB1, we used pan-cancer genomic data from hundreds of patients to show that a single-nucleotide variant in the BCL2 sequence can predict a patient’s response to paclitaxel. Here, we show a connection between this BCL2 genomic variant, its transcript structure, and protein abundance. We demonstrate these findings in silico, in vitro, in formalin-fixed paraffin-embedded (FFPE) tissue, and in patient lymphocytes. We show that tumors with the specific variant are more resistant to paclitaxel. We also show that tumor and normal cells with the variant express higher levels of BCL2 protein, a phenomenon that we validated in an independent cohort of patients. Our results indicate BCL2 sequence variations as determinants of chemotherapy resistance. The knowledge of individual BCL2 genomic sequences prior to the choice of chemotherapy may improve patient survival. The current work also demonstrates the benefit of community-wide, integrative omics data sources combined with in-lab experimentation and validation sets. Nature Publishing Group UK 2019-04-23 /pmc/articles/PMC6478919/ /pubmed/31044156 http://dx.doi.org/10.1038/s41698-019-0084-3 Text en © The Author(s) 2019 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/.
spellingShingle Article
Ben-Hamo, Rotem
Zilberberg, Alona
Cohen, Helit
Bahar-Shany, Keren
Wachtel, Chaim
Korach, Jacob
Aviel-Ronen, Sarit
Barshack, Iris
Barash, Danny
Levanon, Keren
Efroni, Sol
Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types
title Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types
title_full Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types
title_fullStr Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types
title_full_unstemmed Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types
title_short Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types
title_sort resistance to paclitaxel is associated with a variant of the gene bcl2 in multiple tumor types
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478919/
https://www.ncbi.nlm.nih.gov/pubmed/31044156
http://dx.doi.org/10.1038/s41698-019-0084-3
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