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.