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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

01-12-2020 | Breast Cancer | Research article

Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer

Authors: Jason J. Zoeller, Aleksandr Vagodny, Veerle W. Daniels, Krishan Taneja, Benjamin Y. Tan, Yoko S. DeRose, Maihi Fujita, Alana L. Welm, Anthony Letai, Joel D. Leverson, Vincent Blot, Roderick T. Bronson, Deborah A. Dillon, Joan S. Brugge

Published in: Breast Cancer Research | Issue 1/2020

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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.
Appendix
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Metadata
Title
Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer
Authors
Jason J. Zoeller
Aleksandr Vagodny
Veerle W. Daniels
Krishan Taneja
Benjamin Y. Tan
Yoko S. DeRose
Maihi Fujita
Alana L. Welm
Anthony Letai
Joel D. Leverson
Vincent Blot
Roderick T. Bronson
Deborah A. Dillon
Joan S. Brugge
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01374-8

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