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

Mona Foth, Wontak Kim, Kayla T O'Toole

    Biorxiv : the Preprint Server for Biology
    |December 25, 2025
    PubMed

    Insights

    New inhibitors targeting RAS signaling show promise for NRAS-mutated melanoma. However, resistance can emerge, highlighting the need for combination therapies to improve treatment outcomes for these patients.

    Area of Science:

    • Oncology
    • Melanoma Research
    • Molecular Targeted Therapy

    Background:

    • Advanced melanoma often presents with BRAF or NRAS mutations, influencing treatment strategies.
    • While BRAF-mutated melanoma has effective second-line therapies post-immunotherapy failure, NRAS-mutated melanoma lacks targeted options.
    • Immunotherapy is a common first-line treatment for advanced melanoma.

    Purpose of the Study:

    • To evaluate the efficacy of RAS(ON) multi-selective inhibitors, specifically RMC-7977 and daraxonrasib, in NRAS-mutated melanoma.
    • To investigate mechanisms of resistance to RAS-targeted monotherapy.
    • To explore the potential of daraxonrasib as a treatment for NRAS-mutated melanoma.

    Main Methods:

    • Preclinical studies using NRAS-mutated melanoma cell lines and animal models.
    • Assessment of anti-proliferative and anti-tumor activity of RAS inhibitors.
    • Analysis of clinical case studies of patients treated with daraxonrasib.

    Main Results:

    • RMC-7977 and daraxonrasib demonstrated potent anti-proliferative and anti-tumor activity in preclinical NRAS-mutated melanoma models.
    • Resistance to RMC-7977 monotherapy was observed in preclinical models due to mutations in Ppia or Map2k1.
    • Clinical data showed anti-tumor activity in one patient treated with daraxonrasib, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations.

    Conclusions:

    • Daraxonrasib shows potential for treating NRAS-mutated melanoma.
    • Mutations in Ppia (CYPA) and Map2k1 (MEK1) are candidate mechanisms for resistance to RAS-targeted monotherapy.
    • Combination therapies are needed to overcome resistance and improve outcomes for NRAS-mutated melanoma patients.

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