Drugs | Pharmacological Basis and Clinical Translation of Sequential ADC Targeting HER2 and TROP-2

This study systematically elucidates the mechanisms of sequential administration of trastuzumab deruxtecan and sacituzumab govitecan in breast cancer, providing critical theoretical support for overcoming ADC resistance and guiding the precise sequencing of targeted therapies in clinical practice.

 

Literature Overview

The article “Sequential Use of Trastuzumab Deruxtecan and Sacituzumab Govitecan in Patients with Breast Cancer: A Pharmacological Approach to Support the Clinical Rationale,” published in the journal Drugs, systematically explores the potential of sequentially administering two antibody–drug conjugates (ADCs) targeting distinct antigens in breast cancer treatment. The authors analyze the biological basis of HER2 and TROP-2 as independent targets from a pharmacological perspective, integrating resistance mechanisms and clinical evidence to argue that sequential use may remain effective even when both ADCs carry topoisomerase I inhibitors. The article further proposes that differences in target antigens, endocytic pathways, linker chemistry, and bystander effects collectively determine the therapeutic index and resistance profiles of ADCs, offering theoretical support for personalized treatment strategies.

Background Knowledge

Breast cancer is highly heterogeneous, and effective targeted therapies are particularly lacking in HER2-low and triple-negative subtypes, leading to frequent development of drug resistance in advanced patients and an urgent need for novel treatment strategies. Although ADCs have become a key therapeutic modality, their sequential use faces two major challenges: first, potential cross-resistance, especially when the payloads belong to the same class of topoisomerase I inhibitors; and second, the lack of predictive biomarkers to guide the sequence of administration. Moreover, although TROP-2 is highly expressed in various breast cancers, the independence of its regulatory network from that of HER2 has not been fully elucidated, leaving target selection without a solid molecular rationale. This study focuses on systematically comparing the structure–function relationships of the two ADCs to reveal the non-redundancy of their resistance mechanisms, thereby providing pharmacological justification for clinical sequential use, especially in cases involving ABC transporter upregulation or antigen downregulation.

 

 

Research Methods and Experiments

The authors conducted a systematic literature review, integrating studies on ADC resistance mechanisms from the PubMed database between 2015 and August 2025, including clinical trials, translational research, and preclinical models. They focused on analyzing structural differences between trastuzumab deruxtecan and sacituzumab govitecan, including antibody targets, linker types, drug–antibody ratios (DAR), and payload characteristics. Using biomarker data from the DAISY trial, they assessed dynamic changes in HER2 expression before and after treatment, and combined gene network analyses (using String and Cytoscape) to reveal the independence of TACSTD2 (TROP-2) and ERBB2 (HER2) within transcriptional modules. Additionally, in vitro cell models were used to validate the impact of SLX4 mutations on exatecan resistance and the dominant role of ABCG2 in SN-38 efflux.

Key Conclusions and Perspectives

• HER2 and TROP-2 exhibit almost no co-expression or functional crosstalk in gene regulatory networks, supporting their use as non-redundant targets in sequential therapy, suggesting future research should focus on building dynamic monitoring models for dual-target expression.
• Although both ADCs utilize topoisomerase I inhibitors, their resistance mechanisms differ: resistance to trastuzumab deruxtecan is associated with TOPO I mutations, SLX4 deletion, and lysosomal dysfunction, whereas resistance to sacituzumab govitecan is primarily driven by ABCG2-mediated SN-38 efflux, indicating that research should develop specific transporter inhibition models to overcome resistance.
• Real-world clinical data show that regardless of sequence, efficacy of the second-line ADC declines (median PFS decreases from 7.6 to 2.5 months), but PFS is slightly longer when switching targets (3.25 vs. 2.30 months), suggesting research should explore the impact of target switching on the tumor microenvironment.
• The CL2A linker in sacituzumab govitecan allows extracellular release of SN-38, enhancing bystander killing in tumors with heterogeneous TROP-2 expression, whereas trastuzumab deruxtecan relies on cathepsin-B cleavage of the GGFG linker, suggesting future research should develop novel ADCs with controllable release mechanisms.

Research Significance and Prospects

This study provides a solid pharmacological framework for sequential ADC therapy, emphasizing the need to move beyond classifying ADCs solely by payload and instead comprehensively evaluate target antigens, linkers, and resistance mechanisms. From a drug development perspective, it suggests future ADC designs should avoid sharing critical resistance pathways with existing therapies, such as circumventing ABCG2 substrate characteristics. In clinical monitoring, dynamic assessment of HER2 and TROP-2 expression along with ABCG2 levels is recommended to guide treatment sequencing. In disease modeling, composite models that simulate antigen downregulation and transporter overexpression are needed to more accurately reflect clinical resistance processes.

 

 

Conclusion

This study systematically clarifies the pharmacological rationale for the sequential use of trastuzumab deruxtecan and sacituzumab govitecan in breast cancer treatment, emphasizing that despite both targeting topoisomerase I, their distinct targets, endocytic pathways, and resistance mechanisms support non-cross-resistant potential. By revealing the transcriptional independence of HER2 and TROP-2 and the central role of ABCG2 in SN-38 resistance, the study provides molecular evidence for clinical decision-making. In the future, biomarker-driven sequential strategies should be advanced, integrating dynamic antigen detection and resistance gene profiling to achieve precision therapy. Furthermore, these findings guide the development of next-generation ADCs: optimizing linker chemistry to enhance bystander effects and avoid key efflux pumps, thereby extending the therapeutic window. From bench to bedside, this framework will help establish more effective ADC treatment sequences and improve survival outcomes for patients with advanced breast cancer.

 

Marzia Del Re, Elvira Inglese, Emilio Bria, Giuseppe Curigliano, and Romano Danesi. Sequential Use of Trastuzumab Deruxtecan and Sacituzumab Govitecan in Patients with Breast Cancer: A Pharmacological Approach to Support the Clinical Rationale. Drugs.