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Updated: May 23, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Published on: June 7, 2019

Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multiselective Inhibitors in NRAS-Mutated Melanoma

Mona Foth1, Wontak Kim1,2, Kayla O'Toole1,2

  • 1Huntsman Cancer Institute , University of Utah, Salt Lake City, Utah.

Cancer Research
|May 22, 2026
PubMed

Insights

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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