Abstract Triple-negative breast cancer (TNBC) accounts for approximately 10-15% of all breast cancer cases and has a poorer prognosis compared to other breast cancer subtypes. However, there are only limited therapy options for TNBC. The anti-apoptotic protein BCL-xL, a member of the BCL-2 family, has been implicated in promoting tumor cell survival and resistance to chemotherapeutic agents. However, clinical application of current small-molecule BCL-xL inhibitors has been hindered by dose-limiting toxicities, particularly thrombocytopenia resulting from on-target effects in platelets. DT2216 is a novel proteolysis-targeting chimera (PROTAC) designed to degrade BCL-xL in tumor cells while sparing platelets. Here, we aim to evaluate the potential use of DT2216 in the treatment of TNBC patients. Bioinformatics analysis revealed that the BCL-xL gene is highly expressed in TNBC and associated with poor clinical outcomes in TNBC patients. Consistently, BCL-xL expression was also elevated in TNBC cell lines relative to non-TNBC subtypes. BCL-xL knockdown significantly reduced viability of TNBC cell lines (MDA-MB-231 and HS578T) while showing little impact in estrogen receptor (ER)-positive breast cancer cell lines (MCF-7 and T47D), indicating a subtype-specific dependency on BCL-xL. In accordance with these genetic findings, DT2216 markedly inhibited growth of TNBC cell lines while exhibiting minimal effects on ER+ breast cancer cell lines. We further conducted a comprehensive evaluation of the combined effects of DT2216 and standard chemotherapy in TNBC models. DT2216 significantly potentiated the cytotoxic effects of two commonly used chemotherapeutic agents (paclitaxel and carboplatin) across a range of concentrations, producing a robust synergistic inhibition of TNBC cell proliferation. In vivo experiments validating these in vitro data are ongoing. Together, these data indicate that the selective degradation of BCL-xL by DT2216, either as monotherapy or in combination with standard-of-care chemotherapy, could offer a novel therapeutic strategy to improve outcomes for patients with TNBC. Citation Format: Y. Lin, H. Sang, A. Ku, D. Thomas, L. Jia, A. Talab, D. Zhou, B. Lim, Y. Li. Efficacy of a novel BCL-xL degrader, DT2216, in the treatment of triple-negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-09.
Lin et al. (2026) studied this question.