Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy

Jason J Zoeller; Michael F Press; Laura M Selfors; Judy Dering; Dennis J Slamon; Sara A Hurvitz; Joan S Brugge

doi:10.1371/journal.pone.0251163

Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy

PLoS One. 2021 May 5;16(5):e0251163. doi: 10.1371/journal.pone.0251163. eCollection 2021.

Authors

Jason J Zoeller¹, Michael F Press², Laura M Selfors¹, Judy Dering³, Dennis J Slamon³, Sara A Hurvitz³, Joan S Brugge¹

Affiliations

¹ Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, United States of America.
² Pathology, University of Southern California, Los Angeles, California, 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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Antibodies, Monoclonal, Humanized / therapeutic use
Antineoplastic Agents / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Biomarkers, Tumor / metabolism
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism*
Cell Proliferation / drug effects
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lapatinib / therapeutic use
Middle Aged
Neoadjuvant Therapy / methods
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Quinazolines / therapeutic use
RNA, Messenger / metabolism
Receptor, ErbB-2 / metabolism*
Trastuzumab / therapeutic use
Up-Regulation / drug effects

Substances

Antibodies, Monoclonal, Humanized
Antineoplastic Agents
BCL2 protein, human
Biomarkers, Tumor
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Quinazolines
RNA, Messenger
Lapatinib
ERBB2 protein, human
Receptor, ErbB-2
Trastuzumab

Grants and funding

Our work was supported by a Department of Defense Breast Cancer Research Fellowship Award [https://cdmrp.army.mil/bcrp/], Award Number W81XWH-11-1-0572 (to J.J. Zoeller), a Breast Cancer Research Foundation Grant [https://www.bcrf.org] (to M.F. Press) and a Stand Up To Cancer-American Association for Cancer Research Dream Team Translational Cancer Research Grant [https://standuptocancer.org], Grant Number SU2C-AACR-DT0409 (to J.S. Brugge and D.J. Slamon). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.