Head and Neck Squamous Cell Carcinoma (HNSCC), the 6 th most common cancer with 800,000 new cases each year, is an extremely aggressive disease with poor overall survival that has remained unchanged for several decades. For patients that develop recurrent and metastatic (R/M) disease, treatment options are extremely limited, and despite the recent success of immune checkpoint inhibitor (ICI) therapies, overall response rates remain low. To overcome this gap in knowledge and improve survival, our team completed a Phase 2 clinical trial of the pan-VEGF inhibitor, axitinib, in R/M patients. Genetic analysis of tumors from this study revealed that 75% of patients with genomic aberrations in either PIK3CA or PTEN had a longer progression-free survival compared to 17% in those without a PI3K pathway alteration. Importantly, PI3K pathway aberrations are highly prevalent in HNSCC, accounting for 45-55% of all HNSCCs, suggesting the potential for a substantial clinical impact. In our genetically engineered mouse model (GEMM), axitinib significantly extended the overall survival of mice with K14:Pik3ca-H1047R, but not K14:control, tumors. Additionally, the use of in vitro cell proliferation and survival assays in HNSCC cell lines has shown that axitinib reduces cell numbers by 50%, increases gammaH2AX (DNA damage marker) protein levels as measured by western blots, and is more effective in PIK3CA mutant cell lines. Further, when testing the mechanism, we observed that axitinib, but not Lenvatinib (known VEGFR inhibitor), induced apoptosis in HNSCC cell lines. Deeper investigation showed that the HNSCC cell lines did not express any known axitinib targets, suggesting that axitinib may have an additional, unknown mechanism of action (MoA). To test for additional MoA, we used RNA sequencing of axitinib-treated HNSCC cell lines to compare the signal transduction pathways differentially regulated by axitinib compared to other VEGFR and PI3K inhibitors. Future studies will allow us to continue investigating axitinib's mechanism of action and its therapeutic potential in PI3K aberrant HNSCC. Our findings support clinical advancement of axitinib and use of PI3K genetic status as a predictive marker for therapeutic response for a large subset of HNSCC patients with limited therapeutic options.