Abstract B066: Inhibition of farnesyl transferase by tipifarnib leads to isoform specific cell growth inhibition in HRAS-mutated human rhabdomyosarcoma
Authors: Obasaju Patience , Pollard Kai , Allen Amy , Wang Jiawan , Pratilas Christine 
Published: March 2020

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. A subset of RMS expresses the characteristic PAX3-FOXO1 or PAX7-FOXO1 translocations, thought to be oncogenic drivers. Among the fusion-negative subset of RMS, a substantial proportion express oncogenic mutations in RAS proteins or other elements of RAS signaling pathways. Activating RAS mutations are disproportionately seen in patients with high-risk RMS and attempts to augment combination chemotherapy have not resulted in improvement in overall survival in this poor prognosis group. Given the common finding of dysregulated RAS signaling, targeting RAS represents an attractive therapeutic approach. RAS family members require posttranslational modification for plasma membrane localization and subsequent downstream signaling. One therapeutic strategy, therefore, includes disruption of RAS protein prenylation, and thereby its membrane localization, via inhibition of farnesyl transferase (FTase). NRAS and KRAS may utilize geranylgeranyltransferase prenylation as a bypass when FTase is inhibited, but HRAS is uniquely dependent on FTase, and therefore, tumor cells with HRAS mutations may be preferentially sensitive to the effects of farnesyltransferase inhibition (FTI). We therefore tested human RMS cell lines harboring mutations in HRAS, KRAS or NRAS, and those wild type (WT) for H-, K-, and N-RAS, and found that only tumor cells with oncogenic HRAS mutations demonstrate growth inhibition and decreased ERK signaling in response to the FTI tipifarnib. Using high-throughput cell proliferation assays, dose dependent cell growth inhibition in response to treatment with tipifarnib is observed in HRAS-mutated RMS cell lines. We observe a reduction in phosphorylated MEK and ERK in HRAS mutated cell lines indicating effective RAS signaling inhibition. Activity of PI3K-mTOR pathway elements p70-S6K and RPS6 are inhibited by tipifarnib in cell lines that demonstrate an antiproliferative response to the compound. In vivo exposure to tipifarnib in HRAS-mutated RMS xenografts results in tumor growth inhibition. Therapeutic strategies targeting RAS protein prenylation may therefore provide an effective approach as an alternative to traditional chemotherapy, while improving outcomes and decreasing toxicities. Based on these data, a genomically-selected clinical trial using tipifarnib to treat pediatric patients with HRAS-mutated tumors, including RMS, would be of interest.
Citation Format: Patience Obasaju, Kai Pollard, Amy Allen, Jiawan Wang, Christine Pratilas. Inhibition of farnesyl transferase by tipifarnib leads to isoform specific cell growth inhibition in HRAS-mutated human rhabdomyosarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B066. doi:10.1158/1535-7163.TARG-19-B066