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

• Published in: Breast cancer research : BCR Vol. 22; no. 1; pp. 132 - 13
• Main Authors: Zoeller, Jason J, Vagodny, Aleksandr, Daniels, Veerle W, Taneja, Krishan, Tan, Benjamin Y, DeRose, Yoko S, Fujita, Maihi, Welm, Alana L, Letai, Anthony, Leverson, Joel D, Blot, Vincent, Bronson, Roderick T, Dillon, Deborah A, Brugge, Joan S
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.11.2020; BioMed Central; BMC
• Subjects: ABT-263; Analysis; Aniline Compounds - pharmacology; Aniline Compounds - therapeutic use; Animals; Antagonists; Antibodies; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Artificial chromosomes; BCL-2; Bcl-2 protein; Bcl-x protein; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - metabolism; BCL-XL; Biopharmaceutics; Breast - pathology; Breast cancer; Care and treatment; Cytochrome; Cytotoxicity; Drug Resistance, Neoplasm - drug effects; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - analysis; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Female; Histopathology; Homeopathy; Humans; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Materia medica and therapeutics; Mice; Microscopy; Mitochondria; Navitoclax; Patients; Peptides; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - metabolism; Software; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Targeted cancer therapy; Therapeutics; TNBC; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - pathology; Tumors; Viral antibodies; Xenograft Model Antitumor Assays; Xenografts; ADC; BCL-2; BCL-XL; Navitoclax; PDX; ABT-263; Cytotoxic; TNBC; EGFR; Apoptosis
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-020-01374-8

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-X proteins, in order to assess the translational relevance of these combinations for TNBC. 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/X was analyzed in 46 triple-negative patient tumors. 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-X and/or BCL-2. The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/X 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/X inhibitors and systemic chemotherapies.