Critical Recurring Mutation Identified in Head and Neck Cancers – Genetic Engineering & Biotechnology News

Posted: August 2, 2020 at 5:58 pm

Scientists at the University of California-San Diego report that an investigational drug candidate called tipifarnib showed promise in treating head and neck squamous cell carcinoma (HNSCC) tumors with mutations in the HRAS gene. Head and neck cancer is one of the leading causes of cancer-related deaths worldwide, and squamous cell carcinomas account for the majority of these cases.

The study Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas, published in Molecular Cancer Therapeutics, findings shed new light on the HRAS gene, a member of the RAS family of genes that produce proteins that regulate a variety of cellular processes, including growth, movement and differentiation. In 4 to 8 percent of HNSCC tumors, the HRAS gene is mutated.

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, write the investigators.

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.

This preclinical research has the potential to extend to the entire HNSCC patient community, whose overall survival rates are limited in recurrent or metastatic disease, and existing therapeutic options that are far from optimal, with response rates of roughly 10 to 20 percent, said senior co-author J. Silvio Gutkind, PhD, Distinguished Professor of Pharmacology and associate director of basic science at UC San Diego Moores Cancer Center.

These preclinical findings support the idea that HRAS represents a druggable oncogene in HNSCC through tipifarnibs inhibition of a key enzyme. It is a precision therapeutic option for HNSCCs harboring HRAS mutations.

In the study, UC San Diego researchers found that cell line- and patient-derived HNSCC models harboring HRAS mutations were highly sensitive to tipifarnib, which the authors said has demonstrated encouraging preliminary clinical activity in patients with relapsed or refractory HRAS-mutant HNSCC to date.

Currently, Kura Oncology, a San Diego-based biopharmaceutical company, is conducting a nationwide clinical trialto assess the safety and efficacy of tipifarnib in head and neck cancer with HRAS mutations. Employees of Kura are co-authors of the new paper. UC San Diego is not part of the trial.

Treatment with tipifarnib, wrote study authors, had a multifaceted effect on the biology of HRAS-mutant HNSCC tumors, reducing oncogenic signaling and proliferation, while increasing apoptosis, blocking angiogenesis, and driving squamous differentiation of tumors.

Head and neck cancer accounts for approximately 650,000 cases and 330,000 deaths annually worldwide. In the United States, approximately 4 percent of all cancers are head and neck, with an estimated 65,630 persons diagnosed each year, two-thirds of them men and 14,500 deaths, according to Cancer.Net.

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Critical Recurring Mutation Identified in Head and Neck Cancers - Genetic Engineering & Biotechnology News

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