Activating mutations in the HRAS oncogene are present in 5-11% of head and neck squamous cell carcinomas (HNSCC), but whether mutant HRAS drives HNSCC growth was not known. The clinical candidate FTI, tipifarnib, is currently under investigation in HRAS-mutant HNSCC, but whether patient responses to tipifarnib are due to blocking HRAS membrane association or due to action on another FTI target/s is also unclear. We found that the FTIs tipifarnib and lonafarnib inhibited the growth of HRAS-mutant HNSCC in a target-dependent manner, blocking HRAS farnesylation and membrane association. We also found that genetic depletion of mutant HRAS inhibited the anchorage-dependent and -independent growth of HRAS-mutant HNSCC cell lines in vitro and robustly induced apoptosis, indicating HNSCC dependence on mutant HRAS and a correlation between FTI-mediated growth inhibition and blockade of HRAS function. Tumor types driven by other RAS isoforms, such as KRAS-driven pancreatic cancer, are highly dependent on the ERK MAPK effector pathway and are sensitive to pharmacological inhibitors of ERK1/2 (ERKi: SCH772984, BVD-523). In contrast, we found that HRAS-driven HNSCC was resistant to growth inhibition by ERKi alone, despite strong target inhibition as indicated by decreases in pRSK and MYC protein levels. Consistent with this finding, genetic depletion of HRAS not only failed to reduce MAPK signaling but instead caused compensatory upregulation. Similarly, FTI treatment also induced upregulation of MAPK signaling, which is typically growth-promoting. We therefore speculated that the addition of ERKi would enhance responses to FTIs, and indeed found that ERKi synergistically enhanced FTI-mediated apoptosis and growth inhibition. Our results provide a mechanistic rationale for adding ERKi to FTI to improve clinical responses in HRAS-mutant HNSCC, and suggest that monitoring MAPK pathway activation may be a useful marker for emerging FTI resistance in this patient population.

Citation Format: Sehrish Javaid, Victoria V. Nguyen, Andrew M. Waters, Craig M. Goodwin, Channing J. Der, Adrienne D. Cox. Farnesyltransferase inhibitor (FTI)-induced growth inhibition of HRAS-mutant head and neck cancers is enhanced by concurrently inhibiting compensatory upregulation of the ERK-MAPK kinase cascade [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 LB-276.