Sox10-Deficient Drug-Resistant Melanoma Cells Are Refractory to Oncolytic RNA Viruses.
John Abou-HamadJonathan J HodginsEdward YakubovichBarbara C VanderhydenMichele ArdolinoLuc A SabourinPublished in: Cells (2023)
Targeted therapy resistance frequently develops in melanoma due to intratumor heterogeneity and epigenetic reprogramming. This also typically induces cross-resistance to immunotherapies. Whether this includes additional modes of therapy has not been fully assessed. We show that co-treatments of MAPKi with VSV-based oncolytics do not function in a synergistic fashion; rather, the MAPKis block infection. Melanoma resistance to vemurafenib further perturbs the cells' ability to be infected by oncolytic viruses. Resistance to vemurafenib can be induced by the loss of SOX10, a common proliferative marker in melanoma. The loss of SOX10 promotes a cross-resistant state by further inhibiting viral infection and replication. Analysis of RNA-seq datasets revealed an upregulation of interferon-stimulated genes (ISGs) in SOX10 knockout populations and targeted therapy-resistant cells. Interestingly, the induction of ISGs appears to be independent of type I IFN production. Overall, our data suggest that the pathway mediating oncolytic resistance is due to the loss of SOX10 during acquired drug resistance in melanoma.
Keyphrases
- drug resistant
- rna seq
- transcription factor
- single cell
- stem cells
- induced apoptosis
- multidrug resistant
- signaling pathway
- cell cycle arrest
- dna methylation
- skin cancer
- machine learning
- genome wide
- cell death
- pseudomonas aeruginosa
- mesenchymal stem cells
- bone marrow
- deep learning
- cell therapy
- data analysis
- wild type
- smoking cessation