Genotoxic antibody-drug conjugates combined with BCL-XL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer
Year: 2026
Type: article
Abstract: ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive subtype of prostate cancer (PC) without curative treatments. Antibody-drug conjugates (ADCs) emerged as promising cancer therapeutics that selectively deliver cytotoxic agents (payloads) to the tumors. Although ADCs have been successfully applied in the treatment of hematological and solid tumors, ADC monotherapy has not demonstrated durable responses in mCRPC and the mechanisms of PC resistance to ADCs have not been thoroughly investigated. Our study aimed to improve ADC efficacy using a new integrated approach for custom ADC design and multiplexing. To nominate rational combinations of ADC targets and ADC payloads, we (1) examined protein co-expression of three clinically relevant surface antigens— B7 homolog 3 (B7-H3), prostate specific membrane antigen (PSMA), and six-transmembrane epithelial antigen of prostate-1 (STEAP1)—in a series of human mCRPC samples and (2) screened established ADC payloads and their combinations in mCRPC cell lines with different phenotypes. We identified synergistic interactions between DNA-damaging payloads and Bcl-xL inhibitor A-1331852 as well as their coordinated induction of the intrinsic apoptosis pathway. The functional relevance of isolated p53 loss and impaired PC responses to three genotoxic ADCs (B7-H3-seco-DUBA, PSMA-SG3249, and STEAP1-DXd) and their combinations with A-1331852 was established using genetic knockout models. Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC. Significance B7-H3, PSMA, and STEAP1 targeted ADC therapies combining genotoxic payloads with Bcl-xL inhibitors induce p53-dependant apoptotic cell death in mCRPC, providing a clinically viable strategy for the treatment of advanced prostate cancer.
DOI: 10.1172/jci200438
Authors: Galina Semenova, Sander B. Frank, Ruth Dumpit, Wanting Han, Ilsa Coleman, Roman Gulati, Canan D. Dirican, Tarana Arman, Jessica Maruwan, Colm Morrissey, Michael C. Haffner, Peter S. Nelson, John K. Lee
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Defense, Prostate Cancer Foundation, Fred Hutchinson Cancer Research Center, University of Washington, Institute for Prostate Cancer Research, MacroGenics, National Institutes of Health, National Cancer Institute, Congressionally Directed Medical Research Programs, DOD Prostate Cancer Research Program
Awards: G1305388156, G1984635589, G2593043099, G368966876, G4119534169, G6561215213, G6587526009, THE PROSTATE CANCER BIOREPOSITORY NETWORK (PCBN), G7122839000, G8596838845, The Prostate Cancer Biorepository Network (PCBN), Targeting Vulnerabilities Exposed by Cancer Treatment-Induced Lineage Plasticity, Statistical modeling to support population and translational cancer research, Research Specialist in Cancer Genomics to Integrate Basic Research and Clinical Data, Cancer Center Support Grant, The Pacific Northwest Prostate Cancer SPORE
OpenAlex ID: W4414125166