Disrupting Melanoma Defense Mechanism

Melanoma is a very aggressive type of skin cancer that develops from melanocytes – the skin’s pigment-producing cells. Although uncommon, melanoma has the highest mortality rate and the highest potential to spread out of all skin cancers, which verifies that it can be fatal.

Since it is particularly tough to treat when it mutates, melanoma can therefore become treatment-resistant. Although the latest developments in immunotherapy have significantly improved survival rates and results for people with this mutant form of melanoma, there are still those who do not respond as well to these treatments, or whose cancer comes back.

Thomas Graeber, a professor of molecular and medical pharmacology, together with his team of researchers down at UCLA, are studying more on how this cancer changes in order to avoid treatment. The findings were published in the journal Cancer Cell.

The analysis shows that melanoma cells can be broken down into four subgroups, depending on the genes that are activated and deactivated in each differentiation stage.

According to first study author and UCLA researcher Jennifer Tsoi, “This refined characterization improves our understanding of the progressive changes that occur in melanoma cells during dedifferentiation, which can help develop better strategies to target this form of therapy resistance.”

Graeber and his colleagues also analyzed the various levels of drug sensitivity that matched with differentiation stages. The scientists sought drugs that could be used either separately or in combination to target the different stages of melanoma dedifferentiation.

The scientists discovered “a heightened sensitivity to ferroptosis induction with the degree of differentiation.” Ferroptosis is a kind of cell death that can be triggered and is different from the naturally occurring apoptosis — which is the normal cell death that happens when an organism evolves.

They mentioned that discovering this vulnerability to ferroptosis has significant therapeutic implications. They also explained that, as “ferroptosis-inducing drugs” are a great “therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.”

As concluded by the authors, immune therapies get more positive results when used against differentiated cells than non-differentiated ones.