Clinical evaluation of BCL-2/XL 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...

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Published inPloS one Vol. 16; no. 5; p. e0251163
Main Authors Zoeller, Jason J., Press, Michael F., Selfors, Laura M., Dering, Judy, Slamon, Dennis J., Hurvitz, Sara A., Brugge, Joan S.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.05.2021
Public Library of Science (PLoS)
Subjects
Bcl-2 protein
Biology
Biology and Life Sciences
Biopsy
Breast cancer
Cancer
Cancer therapies
Clinical trials
Data analysis
Drug resistance
Editing
ErbB-2 protein
Funding
Geffen, David
Gene expression
Hematology
Informed consent
Medical research
Medicine
Medicine and Health Sciences
Methodology
Oncology
Pathology
Patients
Phenotypes
Proteins
Research and Analysis Methods
Review boards
Tumors
Visualization
Los Angeles California
California
United States > US
Massachusetts
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Abstract 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.
AbstractList 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.
About the Authors: Jason J. Zoeller Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing Affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America Michael F. Press Roles Formal analysis, Funding acquisition, Investigation, Methodology, Writing – review & editing Affiliation: Pathology, University of Southern California, Los Angeles, California, United States of America Laura M. Selfors Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – review & editing Affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America Judy Dering Roles Data curation, Formal analysis Affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America Dennis J. Slamon Roles Funding acquisition, Resources Affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America Sara A. Hurvitz Roles Data curation, Resources, Writing – review & editing Affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America Joan S. Brugge Roles Formal analysis, Writing – review & editing * E-mail: joan_brugge@hms.harvard.edu Affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America Introduction Adaptive responses to targeted-therapies compromise treatment effectiveness and confer drug resistant phenotypes [1]. The number of paired clinical samples available for RNA or protein analysis are described within Tables 1–4. https://doi.org/10.1371/journal.pone.0251163.g001 Materials and methods Biospecimens Tumor biopsies were collected from patients enrolled in the TRIO-B-07 clinical trial (NCT#00769470) as previously described [11]. TRIO-B-07 was reviewed and approved by multiple institutional review boards (UCLA; Olive View; Western), and all participants signed an IRB-approved informed consent form. The Institutional Review Board (IRB) of the Harvard University Faculty of Medicine reviewed and determined that our study is not human subjects research.
About the Authors: Jason J. Zoeller Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing Affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America Michael F. Press Roles Formal analysis, Funding acquisition, Investigation, Methodology, Writing – review & editing Affiliation: Pathology, University of Southern California, Los Angeles, California, United States of America Laura M. Selfors Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – review & editing Affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America Judy Dering Roles Data curation, Formal analysis Affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America Dennis J. Slamon Roles Funding acquisition, Resources Affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America Sara A. Hurvitz Roles Data curation, Resources, Writing – review & editing Affiliation: Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America Joan S. Brugge Roles Formal analysis, Writing – review & editing * E-mail: joan_brugge@hms.harvard.edu Affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America Introduction Adaptive responses to targeted-therapies compromise treatment effectiveness and confer drug resistant phenotypes [1]. The number of paired clinical samples available for RNA or protein analysis are described within Tables 1–4. https://doi.org/10.1371/journal.pone.0251163.g001 Materials and methods Biospecimens Tumor biopsies were collected from patients enrolled in the TRIO-B-07 clinical trial (NCT#00769470) as previously described [11]. TRIO-B-07 was reviewed and approved by multiple institutional review boards (UCLA; Olive View; Western), and all participants signed an IRB-approved informed consent form. The Institutional Review Board (IRB) of the Harvard University Faculty of Medicine reviewed and determined that our study is not human subjects research.
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.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.
Author Zoeller, Jason J.
Slamon, Dennis J.
Brugge, Joan S.
Hurvitz, Sara A.
Selfors, Laura M.
Dering, Judy
Press, Michael F.
AuthorAffiliation Fondazione IRCCS Istituto Nazionale dei Tumori, ITALY
1 Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America
3 Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine University of California, Jonsson Comprehensive Cancer Center, Los Angeles, California, United States of America
2 Pathology, University of Southern California, Los Angeles, California, United States of America
AuthorAffiliation_xml – name: 1 Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America
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Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.A. Hurvitz Contracted Research: Ambrx Amgen Astra Zeneca Arvinas Bayer Daiichi-Sankyo Genentech/Roche Gilead GSK Immunomedics Lilly Macrogenics Novartis Pfizer OBI Pharma Pieris PUMA Radius Sanofi Seattle Genetics Dignitana Zymeworks Phoenix Molecular Designs, Ltd. Stock Options: NK Max Travel: Lilly M.F. Press Consulting or Advisory Role: AstraZeneca Biocartis SA CEPHEID Clinical Care Options, LLC CME Outfitters, LLC Lilly USA, LLC Merck & Co. Puma Biotechnology Zymeworks Inc. Eli Lilly & Company Private Equity Role: TORL BIOTHERAPEUTICS LLC All other authors have declared that no competing interests exist. We have confirmed that the declared competing interests do not alter adherence to all PLOS ONE policies on sharing data and materials.
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RelatedPersons Geffen, David
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Snippet 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...
About the Authors: Jason J. Zoeller Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project...
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SubjectTerms Bcl-2 protein
Biology
Biology and Life Sciences
Biopsy
Breast cancer
Cancer
Cancer therapies
Clinical trials
Data analysis
Drug resistance
Editing
ErbB-2 protein
Funding
Geffen, David
Gene expression
Hematology
Informed consent
Medical research
Medicine
Medicine and Health Sciences
Methodology
Oncology
Pathology
Patients
Phenotypes
Proteins
Research and Analysis Methods
Review boards
Tumors
Visualization
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Title Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy
URI https://www.ncbi.nlm.nih.gov/pubmed/33951110
https://www.proquest.com/docview/2522384281
https://www.proquest.com/docview/2522619066
https://pubmed.ncbi.nlm.nih.gov/PMC8099090
https://doaj.org/article/403191507d6d430fae491ac157d03afe
http://dx.doi.org/10.1371/journal.pone.0251163
Volume 16
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