Payload Diversification Overcomes Resistance and Guides Sequential Antibody-Drug Conjugate Therapy in Breast Cancer

Authors

• Dileep Reddy Rampa
• Minji Seo
• Nanae Ogata
• Zhaoxuan Yang
• Nithya Sridhar
• Fujii Takeo
• Chalothorn Wannaphut
• Jennifer A Maynard
• Kyoji Tsuchikama
• George W Sledge
• Naoto T Ueno
• Jangsoon Lee

Language

English

Publication Date

1-27-2026

Journal

Clinical Cancer Research

DOI

10.1158/1078-0432.CCR-25-3321

PMID

41591991

PMCID

PMC13055631

PubMedCentral® Posted Date

4-8-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Purpose: Antibody-drug conjugates (ADCs) have transformed the treatment of breast cancer. FDA-approved ADCs such as trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) have demonstrated clinical benefit; however, drug resistance will almost inevitably emerge in the metastatic setting, and there is no established strategy for selecting subsequent ADCs after disease progression to the first exposure to the ADC. This study aimed to define mechanisms of acquired resistance and evaluate rational sequencing approaches.

Experimental design: We generated breast cancer cell lines resistant to T-DXd (TDXd-R) and SG (SG-R). We assessed antigen expression, internalization, and resistance pathways, including efflux transporter activity. To identify therapeutic strategies, we tested the efficacy of ADCs carrying non-Topo1 payloads in vitro and in vivo models.

Results: Resistance in both TDXd-R and SG-R models was primarily mediated by payload-specific factors, notably upregulation of efflux transporters, rather than loss of antigen expression. Switching to ADCs with mechanistically different payloads, including microtubule inhibitors, restored antitumor activity in vitro and in vivo.

Conclusions: Cross-resistance to sequential ADCs is primarily driven by shared payload mechanisms rather than loss of the target. Our data also suggest that the clinical benefit of sequential Topo1-based ADCs may be reduced following disease progression on a Topo1-based ADC, likely due to these shared resistance pathways. Importantly, switching to ADCs with non-cross-resistant payload classes may offer a more effective approach to guide ADC sequencing in patients with metastatic breast cancer, supporting payload diversification as a clinically actionable strategy.

Published Open-Access

yes

Recommended Citation

Rampa, Dileep Reddy; Seo, Minji; Ogata, Nanae; et al., "Payload Diversification Overcomes Resistance and Guides Sequential Antibody-Drug Conjugate Therapy in Breast Cancer" (2026). Faculty, Staff and Student Publications. 3427.
https://digitalcommons.library.tmc.edu/uthmed_docs/3427