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Ref Type Journal Article
PMID (32727882)
Authors Gilardi M, Wang Z, Proietto M, Chillà A, Calleja-Valera JL, Goto Y, Vanoni M, Janes MR, Mikulski Z, Gualberto A, Molinolo AA, Ferrara N, Gutkind JS, Burrows F
Title Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas.
Journal Molecular cancer therapeutics
Vol 19
Issue 9
Date 2020 Sep
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS Q61L head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Cell line xenograft Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line xenograft model harboring HRAS Q61L was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth and vessel formation, increased apoptotic activity, and decreased cell proliferation (PMID: 32727882). 32727882
HRAS G12S head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Pdx Actionable In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS G12S was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). 32727882
HRAS K117N head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Pdx Actionable In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS K117N was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). 32727882
HRAS A146T head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Pdx Actionable In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS A146T was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). 32727882
HRAS mutant head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, head and neck squamous cell carcinoma cell lines harboring an HRAS mutation were sensitive to treatment with Zarnestra (tipifarnib), demonstrating reduced cell growth and decreased phosphorylation of Erk and Mek, and inhibition of spheroid viability in culture (PMID: 32727882). 32727882
HRAS G12C head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Cell line xenograft Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line xenograft model harboring HRAS G12C was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth and vessel formation, increased apoptotic activity, and decreased cell proliferation (PMID: 32727882). 32727882
HRAS G13R head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Preclinical - Pdx Actionable In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS G13R was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). 32727882