Abstract 4834: Effective treatment of squamous cell carcinoma of the head and neck (HNSCC) using a combined regimen of tipifarnib and cetuximab

Abstract

Abstract Background: H-RAS driven carcinogenesis has been reported in many types of cancer including squamous cell carcinoma of the head and neck (HNSCC). The mutation rate of H-RAS in HNSCC is 4 - 8%. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). It is known that H-RAS, but not K-RAS and N-RAS, is delocalized into cytoplasm and inactivated by farnesyltransferase inhibitors (FTI), such as tipifarnib. Tipifarnib has demonstrated proof of concept activity in H-RAS mutant HNSCC in an ongoing clinical trial (NCT02383927). In this study, we examined H-RAS associated signaling pathway in HNSCC cell lines and PDX models to see if inhibition of wild-type HRAS signaling could re-sensitize cetuximab resistant cells and tumors to inhibition by cetuximab. UMSCC47 and SCC1-C are both H-RAS wild-type HNSCC cell lines, and SCC1-C is resistant to EGFR targeted therapy. Methods: In vitro cell growth with and without tipifarnib and/or cetuximab treatments were examined by Sulforhodamine B (SRB) and colony formation assay. Patient derived xenograft (PDX) models were then used to study the efficacy of the tipifarnib treatment as a single agent or in combination with cetuximab. Western blot analyses were performed to verify the effect of these treatments on EGFR/ERK/AKT signaling pathways. Results: Our results showed that tipifarnib could inhibit HNSCC growth, both in vitro and in the PDX model in a dose-dependent manner (control vs the low dose of tipifarnib, p = 0.02; control vs the high dose of tipifarnib, p = 0.001). However, the combined treatment with cetuximab significantly enhanced tipifarnib efficacy in the H-RAS wild type setting, particularly in the PDX model (control vs tipifarnib, p = 0.123; control vs cetuximab, p = 0.022; control vs the combination, p = 0.010). Western blot analyses showed that neither ERK nor AKT phosphorylation was effectively reduced after a prolonged treatment (48 hours) with tipifarnib alone. However, the addition of cetuximab reduced pERK. Conclusions: Our study demonstrates that cetuximab enhances the anti-tumor effect of tipifarnib in the H-RAS wild type setting through ERK inhibition. This study supports the rationale for combining tipifarnib with EGFR inhibitors as a possible effective therapeutic approach in HNSCC. Citation Format: Lihua Shu, Dongsheng Wang, Sreenivas Nannapaneni, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen. Effective treatment of squamous cell carcinoma of the head and neck (HNSCC) using a combined regimen of tipifarnib and cetuximab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4834.