Background: HRAS is an important driver oncogene in HNSCC and other squamous cell carcinomas (SCCs). HRAS mutations are observed in 6-10% of HNSCC cases and appear to define a unique subset of HNSCC associated with wild-type TP53, co-mutations in caspase 8 and a characteristic methylation pattern. RAS proteins undergo several posttranslational modifications that facilitate their attachment to membranes. The first and most critical modification is the addition of a farnesyl isoprenoid moiety by the enzyme farnesyltransferase (FT), prompting the development of FTIs for the treatment of RAS-driven cancers. Tipifarnib is a potent and selective FTI that has demonstrated compelling antitumor activity in a heavily pretreated cohort of recurrent/metastatic HNSCC carrying HRAS mutations. Based on these data, a pivotal study (NCT03719690) evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) is currently ongoing. Methods: HRAS is the predominant RAS in squamous epithelial cells and SCCs commonly overexpress the protein. In TCGA PanCancer Atlas, approximately 30% of HNSCC cases have elevated HRAS gene expression, raising the possibility that some HRAS wild-type (WT) HNSCCs may also display a degree of dependence on this oncoprotein. The PI3K-AKT-mTOR pathway is another prominent driver in HNSCC, and reports suggest HRAS and PI3K can each drive resistance to inhibitors of the alternative pathway. In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft (PDX) models alone and in combination with inhibitors of PI3K-a (BYL-719), AKT (GSK2141795) and mTORC1/2 (INK128). Results: Tipifarnib induced regression in several HRAS WT-overexpressing models. In those cases where the FTI was only moderately active, robust inhibition of tumor growth was observed in the majority of animals treated with the combination of tipifarnib and the PI3K-a inhibitor BYL-719. Similar activity was noted in a smaller panel with GSK2141795 & INK128. Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or harbored hotspot mutations or amplification of the PIK3CA gene and in HRAS mutants that carried or lacked PIK3CA mutations. Conclusions: Concomitant blockade of both targets may have surprisingly broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will also be described.