Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck SCCs

Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requiredfor localization to cell membranes. Althoughall RAS isoforms are FT substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS mutant tumors might be susceptible to tipifarnib-mediated inhibition of FT. Here,we report the characterization of tipifarnib activity in awidepanel of HRASmutant and wild type HNSCC xenograft models. Tipifarnib treatment displaced both mutant and wild type HRAS from membranes but only inhibited proliferation, survival and spheroid formation of HRASmutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRASmutant xenografts tested but displayed no activity in six HRASwild type PDX models. Mechanistically, drug treatment resulted in reduction of MAPK pathway signaling, inhibition of proliferation and induction of apoptosis and robust abrogation of neovascularization, apparently viaeffects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FT inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDX. These preclinical findings support that HRASrepresents a druggableoncogenein HNSCC through FT inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRASmutations.