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Updated: Jun 23, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

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Inhibition of the Rho/MRTF pathway improves the response of BRAF-resistant melanoma to PD1/PDL1 blockade

Bardees M Foda1,2, Sean A Misek3,4, Kathleen A Gallo3

  • 1Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.

International Journal of Cancer
|June 20, 2024
PubMed

Insights

Targeting the MRTF pathway with CCG-257081 can overcome resistance to BRAF inhibitors and enhance anti-PD1 immunotherapy in melanoma. This combination therapy reduces tumor growth and improves survival by modulating the tumor immune microenvironment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Metastatic cutaneous melanoma is a deadly skin cancer with limited treatment efficacy due to resistance to targeted and immune therapies.
  • The Rho/Myocardin-related transcription factor (MRTF) pathway is frequently activated in BRAF inhibitor (BRAFi)-resistant melanomas.
  • Pretreatment with BRAFi can diminish the effectiveness of immune checkpoint blockade therapies.

Purpose of the Study:

  • To evaluate the efficacy of concurrent treatment with MRTF pathway inhibitor CCG-257081 and anti-PD1 therapy in a murine melanoma model.
  • To investigate the impact of CCG-257081 on the melanoma immune microenvironment and its potential to enhance anti-PD1 responses.
  • To determine if CCG-257081 can overcome BRAFi resistance and improve outcomes in melanoma.

Main Methods:

  • Utilized a murine vemurafenib-resistant melanoma model.
  • Administered CCG-257081, an MRTF pathway inhibitor, in combination with anti-PD1 immune therapy.
  • Assessed tumor growth, survival rates, and changes in the tumor immune microenvironment, including immune cell infiltration and immune checkpoint protein expression (PDL1).

Main Results:

  • CCG-257081 reduced PDL1 expression on melanoma cells, both sensitive and resistant to BRAFi.
  • Combined treatment with CCG-257081 and anti-PD1 significantly reduced tumor growth and increased survival in the murine model.
  • Co-treatment enhanced the infiltration of CD8+ T cells and B cells into the tumor microenvironment while decreasing tumor-associated macrophages.

Conclusions:

  • CCG-257081 demonstrates potential as an anti-resistance agent in melanoma treatment.
  • Concurrent administration of CCG-257081 with anti-PD1 immunotherapy can enhance clinical responses and improve survival.
  • CCG-257081 modulates the tumor immune microenvironment, making it a promising candidate for combination therapy to overcome melanoma treatment resistance.
Keywords:
MRTFimmunotherapymelanomaresistancerho GTPases

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