Comprehensive Exome Analysis of Immunocompetent Metastatic Head and Neck Cancer Models Reveals Patient Relevant Landscapes

SIMPLE SUMMARY: Head and neck cancer (HNC), once metastasized, is very difficult to treat as there are limited therapy options. Animal models of such can be very useful for preclinical drug development, including precision medicine and immunotherapy. By whole-exome analyses and functional annotation of five commonly used immune-intact metastatic models for HNC research, we aimed to fully annotate their genomic profiles on key cancer genes as well as signaling-, metastasis-, immune- and drug-related events, with direct comparisons with those of patient tumors. Our analyses revealed marked genomic similarities between these models and HNC patient tumors, and identified new potential drug targets for metastatic HNC. We suggest that more of such immune-relevant metastatic HNC models should be developed with full genomic annotations in order to enable preclinical research, and to accelerate precision medicine and immunotherapy development for this devastating cancer. ABSTRACT: Immunocompetent metastatic head and neck cancer (HNC) models, although scarce, can help understanding cancer progression and therapy responses in vivo. Their comprehensive genome characterizations are essential for translational research. We first exome-sequenced the two most widely used spontaneous metastatic immunocompetent models, namely AT-84 and SCC VII, followed by comprehensive genomic analyses with three prior-sequenced models (MOC2, MOC2-10, and 4MOSC2), together with patient tumors for utility assessment. AT-84 and SCC VII bear high HNC tumor resemblance regarding mutational signatures—Trp53, Fanconi anemia, and MAPK and PI3K pathway defects. Collectively, the five models harbor genetic aberrations across 10 cancer hallmarks and 14 signaling pathways and machineries (metabolic, epigenetic, immune evasion), to extents similar in patients. Immune defects in HLA-A (H2-Q10, H2-Q4, H2-Q7, and H2-K1), Pdcd1, Tgfb1, Il2ra, Il12a, Cd40, and Tnfrsf14 are identified. Invasion/metastatic genome analyses first highlight potential druggable ERBB4 and KRAS mutations, for advanced/metastatic oral cavity cancer, as well as known metastasis players (Muc5ac, Trem3, Trp53, and Ttn) frequently captured by all models. Notable immunotherapy and precision druggable targets (Pdcd1, Erbb4, Fgfr1, H/Kras, Jak1, and Map2k2) and three druggable hubs (RTK family, MAPK, and DNA repair pathways) are frequently represented by these models. Immunocompetent metastatic HNC models are worth developing to address therapy- and invasion/metastasis-related questions in host immunity contexts.