Abstract P123: Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated HNSCC

Abstract

Abstract HRAS-MAPK and PI3K-AKT-mTOR are important oncogenic pathways in head and neck squamous cell carcinoma (HNSCC) and other squamous cell carcinomas (SCCs). HRAS is mutated in ~5% and overexpressed in approximately 30% of HNSCC patients, raising the possibility that some HRAS wild-type (WT) HNSCCs may also display a degree of dependence on HRAS. RAS proteins undergo several post-translational modifications, including the addition of a farnesyl isoprenoid moiety by the enzyme farnesyltransferase (FT), which facilitate their attachment to membranes. This dependence prompted the development of selective inhibitors (FTIs) for the treatment of RAS-driven cancers. Tipifarnib is a potent and selective FTI that has demonstrated antitumor activity in recurrent/metastatic HNSCC carrying HRAS mutations. Based on these data, a pivotal study (NCT03719690) evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) is currently ongoing. PIK3CA (the catalytic subunit of PI3K), another prominent driver in HNSCC, is commonly activated either by gain of function mutations or gene amplification with some overlap between the two subsets. Multiple reports indicate that HRAS and PIK3CA pathways cooperate and crosstalk in driving tumor progression in SCCs and resistance to inhibitors of respective pathways. In this study, we explored whether combined inhibition of HRAS farnesylation (by tipifarnib) and inhibition of PI3K pathway signaling (with inhibitors of PI3K-a, AKT or mTORC1/2) would be more effective in CDX and PDX models of HRAS-associated SCCs relative to the monotherapy approaches. In a panel of HNSCC cell lines harboring HRAS and/or PIK3CA alterations (mutation, overexpression or amplification), tipifarnib reduced cell growth and, in combination with PI3K-a inhibitor alpelisib, induced cytotoxicity. Consistent with in vitro findings, robust inhibition of tumor growth was observed in majority of animals treated with the combination of tipifarnib and alpelisib. Similar activity was noted with the AKT inhibitor uprosertib and the mTORC1/2 inhibitor sapanisertib. Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were HRAS mutant or HRAS overexpressed with or without mutation or amplification of the PIK3CA gene or carried the latter without alterations in HRAS, suggesting that concomitant blockade of both targets may have surprisingly broad and potent anti-tumor activity in HNSCC. In dose-scheduling experiments in PDX models, simultaneous blockade of both targets was superior to split intermittent dosing of the two drugs, underlining the cooperativity of the two pathways in these models. Mechanistically, tipifarnib repressed the compensatory MAPK pathway activation induced by alpelisib at the level of phosphorylated ribosomal S6 protein. Impact of tipifarnib and alpelisib combination on additional MAPK and AKT signaling mediators will be reported. Citation Format: Francis Burrows, Shivani Malik, Stacia Chan, Asako Mccloskey, Zhiyong Wang, Mara Gilard, Silvio Gutkind. Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated HNSCC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P123.