As a result of tumor heterogeneity and solid cancers harboring multiple molecular defects, precision medicine platforms in oncology are most effective when both genetic and pharmacologic determinants of a tumor are evaluated. Expandable patient-derived xenograft (PDX) mouse tumor and corresponding PDX culture (PDXC) models recapitulate many of the biological and genetic characteristics of the original patient tumor, allowing for a comprehensive pharmacogenomic analysis. Here, the somatic mutations of 23 matched patient tumor and PDX samples encompassing four cancers were first evaluated using next-generation sequencing (NGS). 19 antitumor agents were evaluated across 78 patient-derived tumor cultures using clinically relevant drug exposures. A binarization threshold sensitivity classification determined in culture (PDXC) was used to identify tumors that best respond to drug in vivo (PDX). Using this sensitivity classification, logic models of DNA mutations were developed for 19 antitumor agents to predict drug response. We determined that the concordance of somatic mutations across patient and corresponding PDX samples increased as variant allele frequency increased. Notable individual PDXC responses to specific drugs, as well as lineage-specific drug responses were identified. Robust responses identified in PDXC were recapitulated in vivo in PDX-bearing mice and logic modeling determined somatic gene mutation(s) defining response to specific antitumor agents. In conclusion, combining NGS of primary patient tumors, high-throughput drug screen using clinically relevant doses, and logic modeling, can provide a platform for understanding response to therapeutic drugs targeting cancer.