Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy Responses

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. HighlightsO_LIMinable multi-omic resource of baseline TNBC PDX tumors matched with single and combination chemotherapy responses yields candidate resistance mechanisms and potentially targetable processes C_LIO_LICombination carboplatin/docetaxel is largely ineffective at enhancing response versus the best single agent in TNBC PDXs, and they can antagonize one another in some PDXs C_LIO_LIProteomics data enhances predictions of platinum- and taxane-based chemotherapy response C_LIO_LITargeted agents can enhance chemotherapy response in TNBC PDXs C_LI