In the United States alone, cancer claims the lives of over 600,000 people a year. While progress has been made in understanding this complex set of diseases, more work is needed if we are to end our struggle with cancer. Bioinformatics analysis and genetically engineered mice are important tools for understanding the biological complexities of cancer. When combined, these approaches can be an important avenue to uncover disrupted cellular pathways contributing to cancer formation. While genetically engineered mouse models are important for the study of cancer, genome sequence analysis of many of these models is lacking. Within this work, we sequenced whole genomes of two genetically engineered mouse models of cancer, MMTV-Neu and MMTV-PyMT. Through this sequence data, we have found numerous disruptions to pathways contributing to the metastatic cascade. These include tumor signatures associated with defective mismatch repair, as well as numerous genomic mutations within cell adhesion genes. More importantly, we have uncovered a conserved V483M missense mutation within the protein tyrosine phosphatase receptor type H (Ptprh) gene. Within mice, tumors harboring a Ptprh mutation correlate with increased phosphorylation of the epidermal growth factor receptor (EGFR). EGFR is a known oncogene that is mutated in numerous cancers, including non-small cell lung cancer (NSCLC). Lung cancer is the number one cancer cause of death in the United States. Often, prognosis for lung cancer is poor, often due to late diagnosis. NSCLC patients with mutations in EGFR typically have a more favorable prognosis, due to treatment with tyrosine kinase inhibitors. More research is needed to improve survival rates of lung cancer patients who do not present with mutations in EGFR. Within NSCLC, 5% of patients have mutations in PTPRH, and many of these mutations correlated with increased EGFR activity as well as PI3K/AKT activity. If PTPRH mutant patients have increased activation of EGFR and would benefit from TKI therapy, this presents a unique opportunity to treat a large subset of cancer patients with an FDA approved therapy. CRISPR KO of PTPRH within the H23 lung cancer cell line resulted in increased phosphorylation of EGFR and downstream AKT. Furthermore, PTPRH mutant NSCLC cell lines H1155 and H2228 respond to the tyrosine kinase inhibitor osimertinib. In vivo osimertinib treatment of nude mice injected with H2228 cells also shows partial response, suggesting PTPRH mutant patients may benefit from EGFR therapy.
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