Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma

Patience Odeniyide, Marielle E. Yohe, Kai Pollard, Angelina V. Vaseva, Ana Calizo, Lindy Zhang, Fausto J. Rodriguez, John M. Gross, Amy N. Allen, Xiaolin Wan, Romel Somwar, Karisa C. Schreck, Linda Kessler, Jiawan Wang, Christine A. Pratilas

Research output: Contribution to journalArticlepeer-review

Abstract

Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with RMS.

Original languageEnglish (US)
Pages (from-to)2973-2983
Number of pages11
JournalOncogene
Volume41
Issue number21
DOIs
StatePublished - May 20 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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