Abstract Trastuzumab deruxtecan (T-DXd), an antibody drug conjugate (ADC), has transformed the treatment landscape for HER2-positive cancers. However, its long-term efficacy is limited by the inevitable development of resistance, which is often driven by altered internalization dynamics, impaired payload activation, or drug efflux. Therefore, next-generation ADCs capable of overcoming these resistance mechanisms are urgently needed to extend durable benefit. We have developed a next-generation degrader antibody conjugate (DAC) that combines a HER2 targeting antibody, trastuzumab, and a selective BRD4 molecular glue degrader, bromoseradeg (BsD), as the payload. BsD is a highly potent, covalent BRD4 degrader and exhibits single digit nanomolar (nM) or sub-nM potency across diverse HER2+ cancer models. Trastuzumab bromoseradeg (T-BsD) was synthesized by cysteine conjugation chemistry via the cleavable Valine-Citrulline-para-aminobenzyl carbamate (Val-Cit-PABC; VCP) linker with an average drug-to-antibody ratio (DAR) of ∼4. T-BsD preserved strong Her2-dependent cytotoxicity and consistently outperforming T-DXd in multiple HER2+ cell models and is also highly active in the T-DXd-insensitive xenograft model. To directly interrogate different resistance mechanisms, we first engineered HER2+ cancer lines to carry the clinically relevant TOP1 R364H mutation, which abolishes TOP1 inhibitor binding and confers robust T-DXd resistance. T-BsD retained cytotoxic potency in these mutant cells ex vivo and showed no loss of antitumor activity in corresponding xenograft models. Separately, we also evaluated resistance driven by overexpression of the efflux transporter ABCC1, a common mechanism that exports the DXd payload. In HER2+ cells with high ABCC1 expression, T-Dxd activity was abrogated, whereas T-BsD completely bypassed ABCC1-mediated efflux and maintained potent activity in both 2D culture and 3D xenograft tumors. Collectively, these compelling preclinical findings establish T-BsD as a mechanistically distinct therapeutic agent designed to overcome potentially key drivers of acquired resistance. By integrating potent BRD4 degradation with HER2-targeted delivery, T-BsD achieves superior activity and effectively bypasses the two most clinically relevant T-DXd resistance pathways. Together, these data strongly support the selective BRD4 degrader as a promising payload for developing next-generation ADCs that can benefit patients who are refractory or resistant to current ADC therapies. Citation Format: Xin Yu, Bin Yang, Wendi Ni, Haibo Liu, Jan Willem Theunissen, Jesse Chen, Jin Wang. A novel covalent BRD4 degrader-HER2-targeting antibody-drug conjugate (DAC) overcomes trastuzumab deruxtecan resistance in HER2-positive cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2406.
Yu et al. (Fri,) studied this question.