Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas
| Autor: | Yusuke Goto, Napoleone Ferrara, Juan Luis Calleja-Valera, Alfredo A. Molinolo, J. Silvio Gutkind, Anastasia Chilla, Zhiyong Wang, Marco Proietto, Matthew R. Janes, Antonio Gualberto, Marco Vanoni, Zbigniew Mikulski, Francis Burrows, Mara Gilardi |
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| Přispěvatelé: | Gilardi, M, Wang, Z, Proietto, M, Chillà, A, Calleja-Valera, J, Goto, Y, Vanoni, M, Janes, M, Mikulski, Z, Gualberto, A, Molinolo, A, Ferrara, N, Gutkind, J, Burrows, F |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research Farnesyltransferase Cellular differentiation Cell Quinolones Mice 0302 clinical medicine Precision Medicine Cancer biology Chemistry Pharmacology and Pharmaceutical Sciences targeted therapy medicine.anatomical_structure Oncology Head and Neck Neoplasms 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Development of treatments and therapeutic interventions Sequence Analysis medicine.drug Cell Survival MAP Kinase Signaling System Oncology and Carcinogenesis Antineoplastic Agents Article Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Rare Diseases Prenylation medicine Genetics Animals Humans HRAS Oncology & Carcinogenesis Dental/Oral and Craniofacial Disease Ra Cell Proliferation Alkyl and Aryl Transferases Oncogene Sequence Analysis RNA Squamous Cell Carcinoma of Head and Neck medicine.disease Head and neck squamous-cell carcinoma 030104 developmental biology Mutation biology.protein Cancer research RNA Tipifarnib |
| Zdroj: | Molecular cancer therapeutics, vol 19, iss 9 Mol Cancer Ther |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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