Thesis defense - Cyrille BERRA

Cyrille BERRA

Ferroptosis as a therapeutic opportunity to counteract BRAFi-resistance in melanoma

 

Nearly half of all diagnosed cutaneous melanomas carry an activating alteration at codon V600 of the gene encoding the BRAF protein kinase. This has led to the era of inhibitors specifically targeting the mutated form of the protein, thereby revolutionizing the treatment of this disease. However, the efficacy of these targeted therapies remains limited by the rapid emergence of resistance mechanisms. This clinical reality underlines the urgent need to develop new therapeutic strategies to overcome resistance and improve patient survival. In this study, we show that mitochondrial activity, accumulation of reactive oxygen species (ROS) and increased lipid peroxidation lead to greater vulnerability to the death by ferroptosis in BRAF inhibitor-resistant melanoma cells. Thus, we have shown that ferroptosis represents a therapeutic opportunity to target resistant cells, which show increased sensitivity to chemical inducers of this form of cell death. Furthermore, our results strongly suggest that the transcription factor Aryl Hydrocarbon Receptor (AhR), which we have already shown to be involved in the acquisition of resistance to targeted therapies, also plays a role in the emergence of this vulnerability.

 

  • Présidente : Marie-Thérèse DIMANCHE-BOITREL, DR, UMR_S 1085 Inserm Irset, Univ. Rennes
  • Examinateurs : 
    • Fabrice JOURNE, DR, Service d'anatomie humaine et d'oncologie expérimentale, Univ. de Mons
    • Julien ABLAIN, CR, U1052 INSERM, UMR5286 CNRS, Univ. Claude Bernard Lyon 1
  • Rapportrices : 
    • Laurence NIETO, PU, Univ. Toulouse III, UMR 1037 INSERM CRCT
    • Sophie VAULONT, DR, Institut Cochin, UMR Inserm U1016, CNRS UMR8104 et Univ. Paris Cité UMR-S 1016