Combined Inhibition of HRAS and MEK Induces Tumor Regression and Restores Myogenic Differentiation in HRAS-Mutant...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Hyperactive RAS signaling, driven by NRAS, HRAS, or KRAS mutations, is a key driver in most PAX3/7::FOXO1 fusion-negative rhabdomyosarcomas (FN-RMS).
• Current indirect RAS pathway therapies have shown limited efficacy in RAS-driven RMS, necessitating novel therapeutic approaches.

Purpose of the Study:

• To investigate the adaptive resistance mechanisms limiting the efficacy of farnesyltransferase inhibitors (FTIs) in HRAS-mutant FN-RMS.
• To evaluate the potential of combining FTIs with MEK inhibitors (MEKi) to overcome FTI resistance and enhance antitumor effects.

Main Methods:

• Utilized preclinical models of HRAS-mutant FN-RMS to study adaptive resistance to FTIs.
• Investigated the role of ERK signaling reactivation and wild-type (WT) RAS upregulation in FTI resistance.
• Assessed the efficacy of combining FTase inhibition with MEK inhibition in preclinical models.

Main Results:

• FTI treatment led to adaptive feedback reactivation of ERK signaling and upregulation of WT RAS, limiting durable antitumor effects.
• The combination of FTI and MEKi effectively suppressed ERK reactivation and reduced ERK transcriptional output in HRAS-mutant RMS models.
• Combined FTase and MEK inhibition restrained tumor progression and induced terminal myogenic differentiation in preclinical models.

Conclusions:

• Adaptive resistance to FTIs in HRAS-mutant RMS is mediated by ERK signaling reactivation and WT RAS upregulation.
• Combining FTase inhibitors with MEK inhibitors presents an effective combinatorial strategy to overcome resistance.
• This combination therapy warrants preclinical translation for patients with HRAS-mutant RMS.