Inhibitors of IAP/XIAP enhance activity of sacituzumab govitecan

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ID: 324334
2026
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Abstract
Abstract TROP2 antibody-drug conjugate sacituzumab govitecan (SG) is approved for treatment of advanced breast cancer. However, intrinsic and acquired resistance occur, leading to a need for novel therapies. We hypothesized that antagonists of inhibitor of apoptosis protein (IAP) enhance the activity of SG and its payload. In this preclinical study, we employed breast cancer models, including patient-derived xenografts (PDXs) and cell lines, to conduct combination therapies with SG and IAP inhibitors. In PDXs, birinapant enhanced the antitumor activity of several chemotherapeutics, especially irinotecan, a metabolic precursor of payload SN-38. We subsequently demonstrated that combinations of SG with birinapant or tolinapant had greater antitumor activity and significantly prolonged event-free survival compared with SG alone. In vitro, IAP antagonists significantly synergized with SG on inhibition of cell viability and colony formation, and on apoptosis induction. These findings suggest that SG combination with IAP inhibitors may represent an effective therapeutic strategy for breast cancer.
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Authors Ming Zhao, Bailiang Wang, Kurt W. Evans, Stephan Scott, Erkan Yuca, Gabriela Raso, Yasmeen Qamar Rizvi, Xiaofeng Zheng, Dali Li, Jun Li, Han Liang, Argun Akçakanat, Michelle Brockman, Senthil Damodaran, Funda Meric-Bernstam
Journal JNCI Journal of the National Cancer Institute
Year 2026
DOI
10.1093/jnci/djag266
URL
https://doi.org/10.1093/jnci/djag266
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