Oral tumors account for approximately 6% of all neoplasms in dogs, and oral squamous cell carcinoma (OSCC) is by far the most common oral malignancy of epithelial origin. OSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. Treatment of choice depends on stage of progression, and may include wide surgical excision (i.e., mandibulectomy or maxillectomy), chemotherapy, radiation therapy or any combination thereof. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. Moreover, many patients may not be considered suitable candidates for standard therapy, or their owners may reject treatment entirely, thus being left with palliative care or euthanasia as the only humanely viable options. [Identification of a non-surgical, targeted therapy with minimal side effects would vastly improve therapeutic options available for this common and aggressive canine malignancy.] OSCC tumors have significant upregulation of the RAS-RAF-MAPK signaling axis, and we hypothesize that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. [In support of our hypothesis, we have found] that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several aggressive OSCC cell lines derived from canine patient tumor samples. The overall aim of this 2-year project is to translate these findings to the clinic, by conducting trials examining the therapeutic efficacy of trametinib for growth inhibition of canine OSCC. We propose two specific aims: 1) [Evaluate the response and tolerability of trametinib in canine patients diagnosed with OSCC], 2) [Improve understanding of OSCC subtypes to assist diagnosis, prognosis, patient stratification and clinical decision making.] Given the imperfect treatment options currently available, this project is of high veterinary and translational value.