3111 Background: Patient-derived xenografts (PDXs) are increasingly being used in translational cancer research for preclinical drug efficacy studies. The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (NCI PDMR; pdmr.cancer.gov ) of PDXs with clinical annotation, proteomics, and comprehensive genomic datasets to facilitate these studies. Here, we present an integrative genomic, transcriptomic, and proteomic analysis of critical signaling and DNA damage repair pathways in these PDX models, which represent 9 common and multiple rare tumor histologies. Methods: 304 PDX models from 294 patients were established from various solid tumor histologies from patients with primary or metastatic cancer. Whole Exome Sequencing, RNA-Seq and Reverse Phase Protein Array (RPPA) were performed on 2-9 PDXs per model across multiple passages. An integrative workflow was applied on multiple data sets to detect pathway activation. Results: We profiled 10 signaling and 5 DNA repair pathways in the PDMR dataset. We observed that: (i) a large fraction (40%) of PDX models have at least 1 targetable mutation in the RTK/RAS and/or PIK3CA pathways; (ii) 131 models (45%) have putative driver and oncogenic mutations and copy number variants (CNVs) in the WNT, TGFRb , NRF2 and NOTCH pathways. In addition, 17% of PDX models have targetable mutations in DNA damage repair pathways and 20 PDMR models have a DNA mismatch repair defect (MSI-H). We confirmed activation of the signaling pathways in a subset of PDX models by pathway enrichment analysis on gene expression data from RNASeq and phosphoprotein-specific antibody binding data from RPPA. Activation of DNA repair processes was confirmed by enrichment of relevant mutational signatures and loss of heterozygosity in these PDX models. Conclusions: Genomic analysis of NCI PDMR models revealed that a large fraction have clinically relevant somatic alterations in key signaling and DNA damage repair pathways. Further integrative analyses with matched transcriptomic and proteomic profiles confirmed pathway activation in a subset of these models, which may prioritize them for preclinical drug studies.