Related Experiment Video
Updated: May 23, 2026
06:09
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma.
Mona Foth1, Wontak Kim1, Kayla O'Toole2
1University of Utah Salt Lake City, UT United States.
Cancer Research
|May 22, 2026
Summary
New drugs targeting NRAS-mutated melanoma show promise, inhibiting RAS signaling. However, resistance can develop, highlighting the need for combination therapies to improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Advanced melanoma often presents with BRAF or NRAS mutations, impacting treatment strategies.
- While BRAF-mutated melanoma has targeted therapies, NRAS-mutated melanoma lacks effective options after immunotherapy failure.
- RAS(ON) inhibitors targeting RAS[GTP] signaling in conjunction with cyclophilin A (CYPA) offer new therapeutic avenues.
Purpose of the Study:
- To evaluate the anti-proliferative and anti-tumor activity of RAS(ON) inhibitors in NRAS-mutated melanoma.
- To identify mechanisms of resistance to RAS(ON) inhibitor monotherapy.
- To assess the clinical potential of daraxonrasib in NRAS-mutated melanoma.
Main Methods:
- In vitro testing of RMC-7977 and daraxonrasib against NRAS-mutated melanoma cell lines.
- In vivo evaluation of anti-tumor efficacy in preclinical melanoma models.
- Analysis of clinical case studies of patients with NRAS-mutated melanoma treated with daraxonrasib.
Main Results:
- Both RMC-7977 and daraxonrasib exhibited potent anti-proliferative and anti-tumor effects in preclinical models.
- Resistance to RMC-7977 monotherapy was associated with mutations in Ppia (CYPA) or Map2k1 (MEK1).
- Clinical data showed anti-tumor activity in one patient treated with daraxonrasib, while another with co-occurring NRAS and MAP2K1 mutations experienced disease progression.
Conclusions:
- Daraxonrasib demonstrates potential for treating NRAS-mutated melanoma.
- Mutations in CYPA and MEK1 are potential mechanisms of resistance to RAS(ON) inhibitors.
- Combination therapies are crucial for overcoming resistance and improving outcomes in NRAS-mutated melanoma.
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