Abstract 4917: Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models

Abstract

Abstract Genomic profiling of squamous tumors has revealed important similarities between lung squamous cell carcinoma (LSCC) and head and neck squamous cell carcinoma (HNSCC). For instance, HRAS is the most commonly mutated RAS species in both LSCC and HNSCC, observed in approximately 2% and 5% of cases, respectively (TCGA, Nature 2013). Tipifarnib is a potent and selective inhibitor of farnesyltransferase (FT) that catalyzes the post-translational attachment of farnesyl groups to proteins that require localization to the inner cell membrane. Although all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. With limited treatment options, LSCC and HNSCC remain a significant unmet medical need. Recent evidence supports the clinical utility of tipifarnib for treatment of patients with HRAS-mutant HNSCC, and we present herein data supporting a potential utility of tipifarnib in the treatment of HRAS-mutant LSCC. We have characterized the antitumor activity of tipifarnib in CDX and PDX models of squamous cell carcinoma with activating HRAS mutations. Tipifarnib displayed robust antitumor activity in the majority of these models, including lung and head and neck tumors. Six of seven HRAS-mutant lung SCC PDX models responded to tipifarnib treatment with the majority either fully growth-inhibited or undergoing partial or complete regression. Importantly, even LSCC PDX tumors resistant to chemotherapy responded to tipifarnib, suggesting tipifarnib has the potential to offer clinical benefit in patients relapsed or refractory to standard therapies. The activity of tipifarnib in LSCC models is quite similar to that seen in HNSCC PDX models, where tipifarnib also induced regressions consistent with those observed in patients enrolled in the ongoing Phase 2 study in HRAS-mutant SCCHN patients (NCT02383927), including patients refractory to chemotherapy, cetuximab and/or immunotherapy. These data demonstrate that HRAS is a targetable mutation in lung SCC as well as in HNSCC and illustrate the potential for tipifarnib in the treatment of additional HRAS-mutant squamous cell carcinomas. Citation Format: Linda Kessler, Catherine Scholz, Antonio Gualberto, Yi Liu, Francis Burrows. Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4917.