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 HRASmutant 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 HRASmutant 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 tipifarnibtreated 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.

The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells

“…These inhibitors seem particularly interesting for targeting the HRas isoform, which is a more potent activator of PI3K than KRas isoform ( Yun et al, 1998 ). Although new powerful approaches for inhibiting Ras signaling in cancer have been recently developed ( Gilardi et al, 2020 ; Shin et al, 2020 ) the challenge for the identification of inhibitors effective on the non-G12C pathological Ras variants is still open.…”

Emerging RAS-directed therapies for cancer

“…Attempts were made to target these enzymes with geranylgeranyltransferase inhibitors, but these were ineffective and associated with toxicity [24] . In contrast, H-RAS is not a substrate for geranylgeranyl transferase and therefore its membrane localization could be suppressed solely by FTIs [25] . Tipifarnib has demonstrated preclinical activity against a wide panel of H-RAS-mutated head and neck squamous cell carcinoma xenograft models and is undergoing clinical development in advanced head and neck cancers harbouring activating H-RAS mutations (NCT02383927) [26] .…”

Promotion of cancer cell stemness by Ras

“…HRAS is the most frequently mutated (5.1%) RAS gene in head and neck squamous cell carcinomas [ 10 ]. Recently, the farnesyltransferase inhibitor tipifarnib has been reintroduced for treatment of HRAS mutant cancers [ 11 ]. While tipifarnib can affect several farnesylated proteins, it is interesting to note that it down-regulated CSC marker CD44 [ 11 ].…”

“…Recently, the farnesyltransferase inhibitor tipifarnib has been reintroduced for treatment of HRAS mutant cancers [ 11 ]. While tipifarnib can affect several farnesylated proteins, it is interesting to note that it down-regulated CSC marker CD44 [ 11 ]. Expression of markers like CD44, CD133/prominin-1 or of classical pluripotency markers such as OCT4, SOX2 and NANOG are used to characterize stemness in cancer cells [ 12–15 ].…”