Related Experiment Video
Updated: Jun 22, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy
Jonathan T Lei1,2, Lacey E Dobrolecki1, Chen Huang1,3
1Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Combination chemotherapy remains essential for clinical management of triple-negative breast cancer (TNBC). Consequently, responses to multiple single agents cannot be delineated at the single patient level, even though some patients might not require all drugs in the combination. Herein, we conduct multi-omic analyses of orthotopic TNBC patient-derived xenografts (PDXs) treated with single agent carboplatin, docetaxel, or the combination. Combination responses were usually no better than the best single agent, with enhanced response in only ~13% of PDX, and apparent antagonism in a comparable percentage. Single-omic comparisons showed largely non-overlapping results between genes associated with single agent and combination treatments that could be validated in independent patient cohorts. Multi-omic analyses of PDXs identified agent-specific biomarkers/biomarker combinations, nominating high Cytokeratin-5 (KRT5) as a general marker of responsiveness. Notably, integrating proteomic with transcriptomic data improved predictive modeling of pathologic complete response to combination chemotherapy. PDXs refractory to all treatments were enriched for signatures of dysregulated mitochondrial function. Targeting this process indirectly in a PDX with HDAC inhibition plus chemotherapy in vivo overcomes chemoresistance. These results suggest possible resistance mechanisms and therapeutic strategies in TNBC to overcome chemoresistance, and potentially allow optimization of chemotherapeutic regimens.
Insights
Combination chemotherapy for triple-negative breast cancer (TNBC) often shows no benefit over single agents. Multi-omic analysis identified biomarkers and potential strategies to overcome chemoresistance, optimizing treatment for TNBC patients.
Area of Science:
- Oncology
- Genomics
- Proteomics
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) treatment relies on combination chemotherapy.
- Current approaches lack patient-specific drug response delineation, potentially leading to suboptimal regimens.
- Identifying biomarkers for treatment response is crucial for personalized TNBC therapy.
Purpose of the Study:
- To conduct multi-omic analyses on TNBC patient-derived xenografts (PDXs) treated with single-agent or combination chemotherapy.
- To identify predictive biomarkers for response to carboplatin, docetaxel, and their combination.
- To explore mechanisms of chemoresistance and potential therapeutic strategies in TNBC.
Main Methods:
- Multi-omic (transcriptomic, proteomic) analyses of TNBC PDXs treated with carboplatin, docetaxel, or combination therapy.
- Validation of identified biomarkers in independent patient cohorts.
- Investigation of chemoresistance mechanisms, including mitochondrial dysfunction, and testing of combination therapies with HDAC inhibitors.
Main Results:
- Combination chemotherapy demonstrated limited added benefit over the best single agent in most PDXs, with some showing antagonism.
- High Cytokeratin-5 (KRT5) expression was identified as a potential general biomarker for treatment responsiveness.
- Integration of proteomic and transcriptomic data improved prediction of pathologic complete response.
- Chemoresistant PDXs exhibited signatures of dysregulated mitochondrial function.
Conclusions:
- Combination chemotherapy regimens for TNBC may not always be superior to single agents, necessitating biomarker-guided selection.
- Multi-omic analyses can identify agent-specific biomarkers and improve predictive modeling for TNBC treatment response.
- Targeting mitochondrial dysfunction presents a potential strategy to overcome chemoresistance in TNBC.
