Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-
- PDF / 4,961,664 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 26 Downloads / 166 Views
RESEARCH ARTICLE
Open Access
Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triplenegative breast cancer Jason J. Zoeller1, Aleksandr Vagodny1, Veerle W. Daniels2, Krishan Taneja3, Benjamin Y. Tan3, Yoko S. DeRose4, Maihi Fujita4, Alana L. Welm4, Anthony Letai2, Joel D. Leverson5, Vincent Blot5, Roderick T. Bronson6, Deborah A. Dillon3 and Joan S. Brugge1*
Abstract Background: Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-XL proteins, in order to assess the translational relevance of these combinations for TNBC. Methods: The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/XL was analyzed in 46 triple-negative patient tumors. Results: Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2. Conclusions: The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/XL antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/XL inhibitors and systemic chemotherapies. Keywords: BCL-2, BCL-XL, ABT-263, Navitoclax, Apoptosis, TNBC, ADC, EGFR, Cytotoxic, PDX
* Correspondence: [email protected] 1 Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence
Data Loading...
