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

Abstract

Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Here, we report the characterization of tipifarnib activity in a wide panel of HRAS-mutant and wild-type head and neck squamous cell carcinoma (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 patient-derived xenograft (PDX) models. Mechanistically, drug treatment resulted in the reduction of MAPK pathway signaling, inhibition of proliferation, 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 FTase inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDXs. These preclinical findings support that HRAS represents a druggable oncogene in HNSCC through FTase inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.

• Authors: Mara Gilardi, Zhiyong Wang, Marco Proietto, Anastasia Chillà, Juan Luis Calleja-Valera, Yusuke Goto, Marco Vanoni, Matthew R Janes, Zbigniew Mikulski, Antonio Gualberto, Alfredo A Molinolo, Napoleone Ferrara, J Silvio Gutkind, Francis Burrows
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 9 Pg. 1784-1796 (09 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32727882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Quinolones
• Alkyl and Aryl Transferases
• p21(ras) farnesyl-protein transferase
• HRAS protein, human
• Proto-Oncogene Proteins p21(ras)
• tipifarnib

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Head and Neck Neoplasms (drug therapy, genetics, metabolism)
• Humans
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mutation
• Precision Medicine
• Prenylation (drug effects)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Quinolones (administration & dosage, pharmacology)
• Sequence Analysis, RNA
• Squamous Cell Carcinoma of Head and Neck (drug therapy, genetics, metabolism)