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

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 …