Background: Molecular drivers in penile squamous cell cancer (PSCC), an orphan malignancy, remain unclear. The Cancer Genome Atlas (TCGA) is not studying PSCC and the Catalogue of Somatic Mutations in Cancer (COSMIC) investigators have reported only targeted analyses of PSCC. We report the first integrated analyses of comprehensive kinomics and whole exome sequencing (seq) in tumors from patients (pts) with PSCC . Methods: We performed integrated functional kinomics profiling and comprehensive exome-seq of two frozen tissue samples from men with PSCC with a matched normal tissue procured from the Cooperative Human Tissue Network (CHTN). Kinomic profiling was performed using the PamStation 12 high-content phospho-peptide substrate microarray system (PamGene International). The protein tyrosine kinome and serine/threonine kinome PamChips were used to measure global kinase activity by detecting phosphorylation of various peptides through FITC-labeled antibodies. Upstream kinase prediction was performed using a scoring algorithm that incorporates the phosphonet database (www.phosphonet.ca). Exome capture was performed with the Agilent SureSelect v5 kit and whole exome-seq was done on the Illumina HiSeq2000 with paired end 100bp chemistry. Results: In the single patient, paired kinomics analysis comparing the tumor sample to adjacent normal tissue, the HER family (EGFR, ERBB2, 3 and 4), AXL, TYRO3 and SYK kinases were the most active. When combining the two tumors in an unpaired analysis against the normal sample, the HER (EGFR, ERBB2, 3 and 4), MER, FRK, and FAK, kinases showed increased activity. When comparing whole exome-seq of the two PSCC samples with normal, among the affected genes were CCDC181, ZNF717, MUC4, HGC6.3, NOTCH1, STK11, SIRPB1, SKA3, PDE6B, FAT1, CACNA2D1, USP17L11, MNT, and CEP89. We are evaluating 10 PSCC tumors and matched normal tissue by kinomics and whole exome-seq and will present these complete data and analysis at the conference. Conclusions: In our preliminary analysis of pts that underwent the first reported integrated kinomics and whole exome-seq performed in PSCC, we identified multiple potential therapeutic targets in tumors.