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Updated: Jul 29, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Signaling Switching from Hedgehog-GLI to MAPK Signaling Potentially Serves as a Compensatory Mechanism in Melanoma

Nikolina Piteša1, Matea Kurtović1, Nenad Bartoniček2,3

  • 1Ruđer Bošković Institute, Division of Molecular Medicine, 10 000 Zagreb, Croatia.

Biomedicines
|May 27, 2023
PubMed
Abstract

Insights

New melanoma cell lines resistant to GANT-61 show altered HH-GLI and MAPK signaling, suggesting new therapeutic targets for combination therapy against this deadly skin cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Melanoma is a deadly skin cancer characterized by cell plasticity, leading to metastasis and chemoresistance.
  • Targeted therapies for melanoma often face resistance, necessitating novel combination strategies.
  • Non-canonical interactions between HH-GLI and RAS/RAF/ERK signaling pathways are implicated in melanoma development.

Purpose of the Study:

  • To investigate the role of non-canonical HH-GLI and RAS/RAF/ERK signaling in melanoma chemoresistance.
  • To explore the potential of combined HH-GLI and RAS/RAF/ERK pathway inhibition as a therapeutic strategy.

Main Methods:

  • Establishment of two melanoma cell lines resistant to the GLI inhibitor GANT-61.
  • Characterization of these resistant cell lines' response to HH-GLI and RAS/RAF/ERK pathway inhibitors.

Main Results:

  • Successfully generated GANT-61 resistant melanoma cell lines.
  • Observed HH-GLI signaling downregulation and increased invasive properties (migration, colony formation, EMT) in resistant cells.
  • Identified differential MAPK signaling activity, cell cycle regulation, and primary cilia formation, indicating diverse resistance mechanisms.

Conclusions:

  • This study presents the first characterization of GANT-61 resistant melanoma cell lines.
  • Potential mechanisms involving HH-GLI and MAPK signaling in chemoresistance were identified.
  • These findings highlight novel non-canonical signaling interactions as potential therapeutic targets in melanoma.
Keywords:
GANT-61HH-GLI pathwayMAPK signalingRAS/RAF/ERK pathwaychemoresistancemelanomaprimary cilia

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