Identifying the Epigenetic Players Involved in Melanoma Resistance to Targeted Therapies and to the Immune System.
Since 2011-2012 and the use of targeted therapies and immunotherapies in the treatment of metastatic melanoma, progress in terms of patient survival is evident, with an increase in median survival from less than a year to over 5 years with immunotherapies. However, almost 50% of patients are in therapeutic dead-end, due to frequent resistance to treatment. The main challenge today is to decipher the mechanisms of resistance to targeted therapies (TC) or immunotherapies (IT) and propose therapeutic approaches to block or reverse these processes.
In 2018, we demonstrated that increased cellular levels of NAD+ render melanoma cells resistant to targeted therapies. This resistance is associated with dedifferentiation and specific epigenetic modifications. Focusing on these non-genetic resistance patterns associated with dedifferentiation, we have identified epigenetic players whose inhibition resensitizes melanoma cells to TCs and increases their immunogenicity.
Our data identify epigenetic players involved in the acquisition of resistance to TC and in the alteration of the immune response in melanoma cells. This results lay the foundations for new therapeutic strategies targeting epigenetic alterations to overcome resistance.
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