Recurring HRAS mutation may drive head and neck cancers
07-31-2020
by Mel J. Yeates  |  Email the author

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SAN DIEGO—In a new study based on preclinical research recently published in Molecular Cancer Therapeutics, researchers at University of California San Diego (UC San Diego) School of Medicine and Moores Cancer Center report that the investigational drug candidate tipifarnib has shown promise in treating head and neck squamous cell carcinomas (HNSCC) tumors with mutations in the HRAS gene. Head and neck cancer is one of the leading causes of cancer-related deaths worldwide, and HNSCCs are responsible for the majority of these cases.
 
The findings shed new light on the HRAS gene, a member of the RAS family of genes that produces 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.
 
“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, Ph.D., 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 tipifarnib’s inhibition of a key enzyme. It is a precision therapeutic option for HNSCCs harboring HRAS mutations.”
 
Tipifarnib is a selective inhibitor of farnesyltransferase, an enzyme that plays a critical role in anchoring some RAS family proteins to cellular membranes. Unlike KRAS and NRAS gene mutations, HRAS is dependent on farnesyltransferase activity for function. This offers a way to indirectly target an oncogenic RAS isoform, using a well-characterized drug with extensive clinical experience.
 
In the study, UC San Diego researchers found that cell line- and patient-derived HNSCC models harboring HRAS mutations were very sensitive to tipifarnib. The authors note that the drug candidate has demonstrated encouraging preliminary clinical activity in patients with relapsed or refractory HRAS-mutant HNSCC.
 
“Tipifarnib displayed robust and consistent antitumor activity in a series of cell line- and patient-derived xenograft models of HNSCC but, in sharp contrast, tipifarnib was devoid of activity in HRAS wild type HNSCC cell lines and PDX models in vitro and in vivo,” the article states. “Remarkably, tipifarnib displayed significant inhibition of tumor growth in HRAS-mutant xenografts harboring mutations in exon-2 (G12C, G12S, G13R), exon-3 (Q61L) or exon-4 (K117N, A146T), suggesting that all of these mutants are sufficiently oncogenic to drive full malignancy in HNSCC cells, even though exon-2 and exon-3/4 KRAS mutants have been reported to have differing GTPase activities and biologic functions in other cellular contexts.”
 
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.
Code: E07312001

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