Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress

Abstract

<p id="P1">Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be sub-classified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase mediated resistance to MAPK targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs presents an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/5f306c24-6959-448b-a683-5d45163ba3b0/PubMedCentral/image/nihms955175u1.jpg"/> </div> </p><p id="P3">Tsoi et al. show that melanoma can be categorized into four subtypes following a differentiation trajectory with subtype-specific sensitivity to ferroptosis induction, which presents a therapeutic approach to target the differentiation plasticity to increase the efficacy of targeted and immune therapies. </p>