Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma
Patience Odeniyide1, Marielle E Yohe2, Kai Pollard1
1Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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.
Insights
Farnesyltransferase (FTase) inhibition with tipifarnib shows promise for treating HRAS-mutant rhabdomyosarcoma (RMS). This targeted approach effectively reduced tumor growth in preclinical models, suggesting a new therapeutic strategy for a specific RMS patient group.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Activating RAS mutations occur in fusion-negative rhabdomyosarcoma (RMS), but direct RAS targeting has lacked clinical success.
- RAS prenylation is essential for its membrane localization and signaling; inhibiting farnesyltransferase (FTase) is a potential therapeutic strategy.
- HRAS is uniquely dependent on FTase for prenylation, unlike NRAS and KRAS, suggesting HRAS-driven tumors may be sensitive to FTase inhibitors.
Purpose of the Study:
- To investigate the mutation-specific effects of FTase inhibition in RMS.
- To evaluate the efficacy of tipifarnib, a selective FTase inhibitor, in preclinical RMS models with characterized RAS mutation status.
Main Methods:
- Utilized in vitro and in vivo models of RMS with defined RAS mutation status.
- Administered tipifarnib to assess its impact on HRAS processing, membrane localization, and downstream signaling.
- Evaluated tipifarnib's effect on cell growth (2D and 3D) and tumor growth in xenograft models.
Main Results:
- Tipifarnib successfully reduced HRAS processing and plasma membrane localization, decreasing GTP-bound HRAS and effector pathway signaling.
- Tipifarnib inhibited cell growth in HRAS-mutant RMS cell lines.
- In vivo, tipifarnib treatment significantly inhibited tumor growth exclusively in HRAS-mutant RMS xenografts.
Conclusions:
- FTase inhibition by tipifarnib demonstrates activity in HRAS-driven RMS.
- Targeting FTase represents a potential therapeutic strategy for a genomically defined subset of RMS patients with HRAS mutations.
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