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Updated: Aug 15, 2026
Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast
Yu-Wen Cai1, Shu-Han Jia1, Hao Wang2
1Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
Abstract:
Antibody-drug conjugates (ADCs) have transformed the treatment of HER2-positive breast cancer, yet resistance remains poorly understood. Using imaging mass cytometry, we profiled 157 regions of interest comprising 912,360 single cells from 47 HER2-positive/hormone receptor-negative breast cancers treated with SHR-A1811 in the FASCINATE-N trial. Spatial proteomic analyses identified two determinants of ADC response: elevated tumor-cell H3K27ac expression was associated with improved ADC efficacy, whereas collagen-positive fibroblasts mediated resistance. Combining ADC with the histone deacetylase inhibitor chidamide or the collagen-modulating agent losartan produced synergistic antitumor effects in preclinical models. These biomarkers and therapeutic vulnerabilities were independently validated in patients with advanced HER2-positive disease receiving trastuzumab deruxtecan. Moreover, based on these spatial features, we developed a clinically applicable ADC barrier prediction model that can be implemented using multiplex immunofluorescence. Taken together, our findings reveal actionable spatial determinants of ADC efficacy and suggest potential combination therapeutic strategies.
Insights
Antibody-drug conjugates (ADCs) show promise for HER2-positive breast cancer, but resistance is a challenge. New research identifies tumor cell H3K27ac and collagen fibroblasts as key factors, suggesting combination therapies for improved efficacy.
Area of Science:
- Oncology
- Cancer Research
- Molecular Biology
Background:
- Antibody-drug conjugates (ADCs) have revolutionized HER2-positive breast cancer treatment.
- Understanding and overcoming therapeutic resistance to ADCs is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the spatial proteomic landscape associated with response and resistance to ADCs in HER2-positive breast cancer.
- To identify predictive biomarkers and therapeutic vulnerabilities for enhancing ADC efficacy.
Main Methods:
- Utilized imaging mass cytometry to profile single cells from HER2-positive breast cancer patients treated with an ADC (SHR-A1811).
- Performed spatial proteomic analyses to identify determinants of ADC efficacy and resistance.
- Validated findings in preclinical models and in patients treated with trastuzumab deruxtecan.
Main Results:
- Elevated tumor-cell H3K27ac expression correlated with improved ADC efficacy.
- Collagen-positive fibroblasts were identified as a mechanism of ADC resistance.
- Combination therapies (ADC with chidamide or losartan) demonstrated synergistic antitumor effects.
- A predictive model for ADC resistance was developed using spatial features.
Conclusions:
- Spatial proteomic features, including H3K27ac and collagen-rich stroma, are critical determinants of ADC response in HER2-positive breast cancer.
- Targeting histone acetylation and stromal collagen presents potential therapeutic strategies to overcome ADC resistance.
- A clinically applicable prediction model can guide treatment decisions and combination therapy selection.
