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.