Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas

SIMPLE SUMMARY: Current therapies for recurrent and metastatic squamous cell carcinomas (SCCs) are associated with poor patient outcomes, and options for later lines of treatment are very limited. In cases where single-agent therapy may be insufficient to eradicate the tumor, thus allowing outgrowth of resistant cells, a well-chosen combination of therapeutic agents may enable improved outcomes. Tipifarnib, a farnesyl transferase inhibitor, is a small molecule drug candidate that has demonstrated promising clinical activity in HRAS-mutant head and neck squamous cell carcinoma (HNSCC). New molecular analyses suggest that HRAS may also be important in some HNSCC cases where it is not mutated, which might allow tipifarnib to be active in a broader population of HNSCC patients when used in combination with other agents such as cisplatin, cetuximab, or alpelisib. Other non-HRAS oncoproteins that can also be blocked by tipifarnib may offer alternative approaches to combination regimens for SCCs. ABSTRACT: Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)–specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.