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Updated: Jul 18, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Gene signature reveals decreased SOX10-dependent transcripts in malignant cells from immune checkpoint
Timothy J Purwin1,2, Signe Caksa1, Ahmet Sacan2
1Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Abstract:
Evidence is mounting for cross-resistance between immune checkpoint and targeted kinase inhibitor therapies in cutaneous melanoma patients. Since the loss of the transcription factor, SOX10, causes tolerance to MAPK pathway inhibitors, we used bioinformatic techniques to determine if reduced SOX10 expression/activity is associated with immune checkpoint inhibitor resistance. We integrated SOX10 ChIP-seq, knockout RNA-seq, and knockdown ATAC-seq data from melanoma cell models to develop a robust SOX10 gene signature. We used computational methods to validate this signature as a measure of SOX10-dependent activity in independent single-cell and bulk RNA-seq SOX10 knockdown, cell line panel, and MAPK inhibitor drug-resistant datasets. Evaluation of patient single-cell RNA-seq data revealed lower levels of SOX10-dependent transcripts in immune checkpoint inhibitor-resistant tumors. Our results suggest that SOX10-deficient melanoma cells are associated with cross-resistance between targeted and immune checkpoint inhibitors and highlight the need to identify therapeutic strategies that target this subpopulation.
Insights
Reduced SOX10 expression in melanoma correlates with resistance to both targeted kinase inhibitors and immune checkpoint inhibitors. This suggests SOX10-deficient cells may drive cross-resistance, necessitating new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cross-resistance between immune checkpoint inhibitors (ICIs) and targeted kinase inhibitors is a growing concern in cutaneous melanoma.
- Loss of the transcription factor SOX10 is linked to resistance against MAPK pathway inhibitors.
Purpose of the Study:
- To investigate the association between reduced SOX10 expression/activity and resistance to ICIs in melanoma.
- To develop and validate a SOX10 gene signature as a biomarker for SOX10-dependent activity.
Main Methods:
- Bioinformatic integration of SOX10 ChIP-seq, knockout RNA-seq, and knockdown ATAC-seq data from melanoma cell models.
- Computational validation of the SOX10 signature in independent datasets including single-cell and bulk RNA-seq, cell line panels, and drug-resistant models.
- Analysis of patient single-cell RNA-seq data to assess SOX10-dependent transcript levels in ICI-resistant tumors.
Main Results:
- A robust SOX10 gene signature was developed and validated as a measure of SOX10-dependent activity.
- Lower levels of SOX10-dependent transcripts were observed in immune checkpoint inhibitor-resistant melanoma tumors.
- SOX10 deficiency is associated with cross-resistance to both targeted and immune checkpoint therapies.
Conclusions:
- SOX10-deficient melanoma cells contribute to cross-resistance between targeted therapies and ICIs.
- Targeting SOX10-deficient melanoma subpopulations may represent a novel therapeutic strategy.
- Further research is needed to develop effective treatments for this resistant melanoma subset.
