Oral squamous cell carcinoma (OSCC) is a common oral tumor in companion dogs, and though it has a comparatively good prognosis, the current standard of care relies heavily on aggressive and invasive surgery, which invariably results in physical deformity and has a high chance of reducing quality of life. We have found that most OSCCs in dogs show high activation of RAS-pathway signaling (e.g., RAS-RAF-MEK-ERK). This led to our clinical trial examining the efficacy of the MEK inhibitor trametinib in dogs. Our results to date show that in approximately 45% of patients, daily treatment with trametinib can result in substantial reduction in tumor volume in as little as two weeks. Our goal in this project is to stratify the patient population to increase the chance of effective drug intervention. Our preliminary results suggest that patients with constitutively active BRAF-mutant tumors have been most responsive to the drug, and so we will recruit a new cohort of dogs with tumors that harbor the mutation to a modified clinical study, in order to make statistically compelling arguments regarding drug efficacy which are not yet possible with current patient numbers. We will modify our clinical approach to provide the drug for twice as long as currently (four months rather than two months) to begin examining the durability of drug effectiveness. And we will search for residual tumor cells in tissue excised following drug treatment in order to determine if the drug is eliminating tumors entirely or leaving residual cells behind, which might result in recurrence. These findings will allow us to make a medically and scientifically sound conclusion regarding the suitability of trametinib monotherapy as a neoadjuvant treatment for OSCC in companion dogs.