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Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy
Our previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected befo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099090/ https://www.ncbi.nlm.nih.gov/pubmed/33951110 http://dx.doi.org/10.1371/journal.pone.0251163 |
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author | Zoeller, Jason J. Press, Michael F. Selfors, Laura M. Dering, Judy Slamon, Dennis J. Hurvitz, Sara A. Brugge, Joan S. |
author_facet | Zoeller, Jason J. Press, Michael F. Selfors, Laura M. Dering, Judy Slamon, Dennis J. Hurvitz, Sara A. Brugge, Joan S. |
author_sort | Zoeller, Jason J. |
collection | PubMed |
description | Our previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected before and after lapatinib or trastuzumab treatment, from the TRIO-B-07 clinical trial (NCT#00769470). We detected BCL2 mRNA upregulation in both HER2+/ER- as well as HER2+/ER+ patient tumors treated with lapatinib or trastuzumab. To address whether mRNA expression correlated with protein expression, we evaluated pre- and post-treatment tumors for BCL-2 via immunohistochemistry. Despite BCL2 mRNA upregulation within HER2+/ER- tumors, BCL-2 protein levels were undetectable in most of the lapatinib- or trastuzumab-treated HER2+/ER- tumors. BCL-2 upregulation was evident within the majority of lapatinib-treated HER2+/ER+ tumors and was often coupled with increased ER expression and decreased proliferation. Comparable BCL-2 upregulation was not observed within the trastuzumab-treated HER2+/ER+ tumors. Together, these results provide clinical validation of the BCL-2 induction associated with the adaptive response to lapatinib and support evaluation of BCL-2 inhibitors within the context of lapatinib and other HER2-targeted receptor tyrosine kinase inhibitors. |
format | Online Article Text |
id | pubmed-8099090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-80990902021-05-17 Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy Zoeller, Jason J. Press, Michael F. Selfors, Laura M. Dering, Judy Slamon, Dennis J. Hurvitz, Sara A. Brugge, Joan S. PLoS One Research Article Our previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected before and after lapatinib or trastuzumab treatment, from the TRIO-B-07 clinical trial (NCT#00769470). We detected BCL2 mRNA upregulation in both HER2+/ER- as well as HER2+/ER+ patient tumors treated with lapatinib or trastuzumab. To address whether mRNA expression correlated with protein expression, we evaluated pre- and post-treatment tumors for BCL-2 via immunohistochemistry. Despite BCL2 mRNA upregulation within HER2+/ER- tumors, BCL-2 protein levels were undetectable in most of the lapatinib- or trastuzumab-treated HER2+/ER- tumors. BCL-2 upregulation was evident within the majority of lapatinib-treated HER2+/ER+ tumors and was often coupled with increased ER expression and decreased proliferation. Comparable BCL-2 upregulation was not observed within the trastuzumab-treated HER2+/ER+ tumors. Together, these results provide clinical validation of the BCL-2 induction associated with the adaptive response to lapatinib and support evaluation of BCL-2 inhibitors within the context of lapatinib and other HER2-targeted receptor tyrosine kinase inhibitors. Public Library of Science 2021-05-05 /pmc/articles/PMC8099090/ /pubmed/33951110 http://dx.doi.org/10.1371/journal.pone.0251163 Text en © 2021 Zoeller et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Zoeller, Jason J. Press, Michael F. Selfors, Laura M. Dering, Judy Slamon, Dennis J. Hurvitz, Sara A. Brugge, Joan S. Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy |
title | Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy |
title_full | Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy |
title_fullStr | Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy |
title_full_unstemmed | Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy |
title_short | Clinical evaluation of BCL-2/X(L) levels pre- and post- HER2-targeted therapy |
title_sort | clinical evaluation of bcl-2/x(l) levels pre- and post- her2-targeted therapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099090/ https://www.ncbi.nlm.nih.gov/pubmed/33951110 http://dx.doi.org/10.1371/journal.pone.0251163 |
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