Mecanismos de resistencia a las terapias dirigidas en melanoma

Melanoma accounts for 80% of skin cancer deaths.  Genetic alterations in MAPK pathway, especially the BRAF^V600E mutation, lead to MAPK hyperactivation and melanoma growth. Targeted therapy with combined BRAF and MEK inhibitors have improved the survival of melanoma patients, but frequent resistance to this therapy causes serious clinical threats. Recent data has revealed that non-genetic mechanisms of transcriptional reprogramming and adaptation can be responsible for cancer resistance. Non-genetic resistance is a reversible state of early therapeutic drug tolerance, provided by cancer cells with minimal growth, that later can develop in genetically-based resistance resulting in disease relapse. The drug-tolerant persister (DTP) cells are defined as those that regenerate the tumor, but remain treatment-sensitive. Thus, the early DTP state opens a promising therapeutic window to refrain resistance in melanoma. To provide a genetic, transcriptional and functional view of DTPs, we have generated an immunocompetent in vivo mouse model of melanoma showing resistance to combined BRAF and MEK inhibitors, which encompasses cells in the early DTP state and in progression to stable resistance. Identification of potential DTP markers for therapeutic studies, and confirmation in human PDX models and samples from melanoma patients treated with BRAF and MEK inhibitors will clinically validate our data.