Here, the inventors have developed a spectral
flow cytometry assay to measure
heme biosynthesis. By using this new
assay on
melanoma cell lines, they observed a direct correlation between high PPIX levels in differentiated MITFhigh cells and a protection against
ferroptosis. Conversely,
cell lines with low PPIX levels were associated with a dedifferentiated MITFlow
phenotype enriched in
stem cell markers and more sensitive to
ferroptosis inducers. They also found that inhibition of PPIX
biosynthesis in differentiated
melanoma cells synergizes with iron overload to induce
lipid peroxidation and
tumor cell death. Finally, they show that decreased levels of PPIX linked to increased
ferroptosis sensitivity can be acquired
in vivo in
melanoma tumors that relapse after anti-MAPK targeted therapies. The present invention relates to a method of determining whether a subject has or is at risk of having melanoma ferroptosis sensitivity and
targeted therapy resistance comprising i) determining the level of
protoporphyrin IX (PPIX) in a biological sample obtained from the subject and ii) comparing the level determined at step i) with a predetermined reference value: wherein if the level of the PPIX determined at step (i) is lower than the predetermined reference value is indicative that the said patient is having melanoma ferroptosis sensitivity and
targeted therapy resistance or wherein if the level of the PPIX determined at step (i) is higher than the predetermined reference value is indicative that the said patient is having melanoma ferroptosis resistance and
targeted therapy sensitivity. The present invention also relates to a method for treating resistant melanoma in a subject in need thereof comprising a step of administering said subject with a therapeutically effective amount of a ferroptosis
inducer.