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

• Published in: PloS 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
• Language: English
• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0251163

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.