Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas.

Published on Sep 1, 2020in Molecular Cancer Therapeutics5.615
· DOI :10.1158/1535-7163.MCT-19-0958
Mara Gilardi11
Estimated H-index: 11
(UCSD: University of California, San Diego),
Zhiyong Wang51
Estimated H-index: 51
(UCSD: University of California, San Diego)
+ 11 AuthorsFrancis Burrows29
Estimated H-index: 29
Sources
Abstract
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 required for localization to cell membranes. Although all 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 a wide panel of HRAS mutant 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 HRAS mutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRAS mutant xenografts tested but displayed no activity in six HRAS wild 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 via effects 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 HRAS represents a druggable oncogene in HNSCC through FT inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.
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