Abstract Background: Chemotherapy is essential for the management of patients with triple-negative breast cancer (TNBC). Identification of biomarkers that may indicate treatment efficacy will be critical to improve patient stratification prior to treatment. To elucidate molecular determinants underlying chemotherapy response, we conducted a proteogenomic study using TNBC patient-derived xenografts (PDXs) treated with chemotherapy. Methods: Orthotopic TNBC PDXs were treated with four weekly cycles of docetaxel, carboplatin, or the combination. Changes in tumor volume after 4 weeks of treatment were evaluated. Genomic, transcriptomic, and mass-spectrometry-based proteomic profiling were performed on baseline tumors prior to treatments to identify associations with chemotherapy response (https://pdxportal.research.bcm.edu). Fisher’s exact test was used to identify significant associations between mutation and copy number events and dichotomized treatment response. For gene level analyses, Spearman’s correlation was calculated between mRNA or protein abundance and log2 fold change in tumor volumes after treatment. Signed -log10 p-values from Spearman’s correlation analysis were used as input for Gene Set Enrichment Analysis. Validation in external datasets was performed using METABRIC (PMID: 22522925) and BrighTNess clinical trial (PMID: 29501363) human datasets, an independent PDX dataset (PMID: 32546838), and shRNA screen data from DepMap (PMID: 30389920). Results: Combination carboplatin and docetaxel was largely ineffective at generating enhanced responses over the best single agent, suggesting de-escalation of chemotherapy may be possible. Genomic aberrations in BRCA2 and BCL9 were enriched in carboplatin-responsive PDXs while aberrations in RAF1 were enriched in docetaxel-resistant PDXs. Genes with gene-drug response correlations supported by both mRNA and protein measurements, but not mRNA or protein alone, for both carboplatin and docetaxel treatment in PDXs were associated with prognosis from basal human breast tumors receiving any chemotherapy from the METABRIC dataset. These data suggest that the combination of mRNA and protein data provided increased accuracy in identifying genes associated with clinical outcome in TNBC. Some of the top genes with genomic aberrations and/or overexpression at both mRNA and protein levels in chemoresistant PDXs, many of which have not been evaluated for their ability to augment response to taxane- or platinum-based chemotherapies, were validated in independent datasets with PDXs and TNBC patients receiving carboplatin and taxane combination. Further, some were found to be dependencies in TNBC cell lines from a publicly available genetic perturbation dataset. At the pathway level, both mRNA and protein data associated models resistant to both agents with enhanced oxidative phosphorylation and proteostatic pathways including proteosome degradation and the unfolded protein response (UPR) pathway related to endoplasmic reticulum stress. Pharmacological targeting the UPR pathway in combination with docetaxel showed activity in PDX models resistant to single-agent docetaxel. These results suggest targeting the UPR pathway as a novel therapeutic strategy to overcome chemotherapy resistance in TNBC. Conclusion: Proteogenomic analysis of PDX tumors identified diverse genes and pathways associated with chemotherapy resistance and response and further suggests potential therapeutic opportunities in TNBC. Citation Format: Jonathan T Lei, Chen Huang, Ramakrishnan R Srinivasan, Suhas Vasaikar, Lacey E Dobrolecki, Alaina N Lewis, Christina Sallas, Susan G Hilsenbeck, C. Kent Osborne, Mothaffar F Rimawi, Matthew J Ellis, Varduhi Petrosyan, Alexander B Saltzman, Anna Malovannaya, Gerburg Wulf, Daniel C Kraushaar, Tao Wang, Xi Chen, Gloria V Echeverria, Meenakshi Anurag, Bing Zhang, Michael T Lewis. Proteogenomic analysis of differential chemotherapy responses in patient-derived xenografts of triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-07-01.