27P - Molecular insights on cutaneous melanoma hyperpigmentation and therapy resistance

Background

Despite notable progress in cutaneous melanoma (CM) treatment with immune checkpoint inhibitors (ICI), resistance onset urges the need for innovative approaches. Melanin involvement in CM progression is significant, as hyperpigmentation correlates with therapy resistance, including resistance to ICI. Melanin serves a dual role, acting as a protective agent against light-induced damage by scavenging reactive oxygen species (ROS) but also as a photosensitizer/pro-oxidative agent depending on its type and intracellular redox state. The melanin ROS-scavenging activity is primarily attributed to its ability to chelate metal ions such as iron, which can induce melanogenesis itself due to its high ROS-generating activity. Experimental evidence suggests that miR-214 is involved in melanoma hyperpigmentation and therapy resistance. This study aims to elucidate the interplay among miR-214, ROS, and iron in hyperpigmented/resistant CM.

Methods

The pigmentation level of control and stably transfected miR-214 cells (miR-214+) was assessed in vitro via melanosomes and intracellular melanin quantification, and correlated with ROS and iron content. CM cell therapy response in vitro was evaluated by 2D/3D assays. Both conventional and innovative nanoparticle-based approaches were used to modulate melanogenesis and assess therapy response. miR-214 plasmatic levels of ICI-treated CM patients at the Careggi University Hospital in Florence were quantified using droplet digital PCR.

Results

miR-214+ melanoma cells showed hyperpigmentation related to a pro-oxidative state and a reduced Glutathione S-transferase Zeta 1 (GSTZ1) expression, an anti-oxidant protein also involved in the catabolism of the melanin precursors phenylalanine and tyrosine. miR-214+ hyperpigmented cells showed less responsiveness to chemo-, target, and radiotherapy in vitro than control, restored when miR-214 signalling and melanogenesis were inhibited. Higher levels of miR-214 were found in plasma samples of ICI-treated non-responder CM patients compared to responders.

Conclusions

miR-214 triggers hyperpigmented, resistant melanoma phenotypes. Understanding its molecular network will be crucial to finding new therapy targets for non-responsive CM patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

E. Andreucci.

Funding

Associazione Italiana per la Ricerca sul Cancro and Fondazione Guido Berlucchi.

Disclosure

All authors have declared no conflicts of interest.