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Sox10-Deficient Drug-Resistant Melanoma Cells Are Refractory to Oncolytic RNA Viruses

John Abou-Hamad1,2, Jonathan J Hodgins1,3, Edward Yakubovich1,2

  • 1Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.

Cells
|January 11, 2024
PubMed

Insights

Melanoma drug resistance hinders oncolytic virus therapy. Loss of SOX10 in resistant melanoma cells impairs viral infection, suggesting a new resistance pathway involving interferon-stimulated genes.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Targeted therapy resistance is a major challenge in melanoma treatment, often leading to cross-resistance to other therapies.
  • The interplay between drug resistance, epigenetic reprogramming, and susceptibility to oncolytic viruses in melanoma is not fully understood.

Purpose of the Study:

  • To investigate the impact of targeted therapy resistance on the efficacy of combined oncolytic virotherapy and targeted therapy in melanoma.
  • To elucidate the mechanisms underlying potential cross-resistance to oncolytic viruses in drug-resistant melanoma.

Main Methods:

  • Co-treatment experiments with BRAF inhibitors (MAPKi) and Vesicular Stomatitis Virus (VSV)-based oncolytic viruses in melanoma models.
  • Analysis of melanoma cell lines with acquired resistance to vemurafenib, including those with SOX10 loss.
  • RNA-sequencing (RNA-seq) to analyze gene expression profiles, focusing on interferon-stimulated genes (ISGs).

Main Results:

  • Combined MAPK inhibitor (MAPKi) and oncolytic virus treatment showed no synergy; MAPKis inhibited viral infection.
  • Melanoma cells resistant to vemurafenib exhibited reduced susceptibility to oncolytic viruses.
  • Loss of SOX10, a melanoma marker, induced cross-resistance to oncolytic viruses by inhibiting viral infection and replication.
  • SOX10-deficient and drug-resistant melanoma cells displayed upregulated interferon-stimulated genes (ISGs), independent of type I interferon production.

Conclusions:

  • Acquired resistance to targeted therapy in melanoma, particularly through SOX10 loss, confers resistance to oncolytic virus therapy.
  • Upregulation of ISGs, independent of type I IFN, is implicated in this oncolytic resistance pathway.
  • Targeted therapies may impede oncolytic virotherapy efficacy in melanoma by interfering with viral infection.
Keywords:
BRAFV600ESOX10drug resistancemelanomaoncolyticsvemurafenib

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