Metastatic melanoma remains a major treatment challenge despite recent therapeutic advances, including the use of immune checkpoint inhibitors (ICIs) and MAPK-targeting drugs. A study published in June investigates the evolutionary pathways to metastasis and ICI resistance using autopsy samples from the Posthumous Evaluation of Advanced Cancer Environment (PEACE) study. Spain, Coulton, Lobon, Rowan, Schnidrig et al. performed extensive sampling of late-stage melanomas and metastases from 14 patients, and used several omics approaches to investigate the genetic changes that occur in metastasis and therapy resistance.
Whole-genome duplication was present in most patients (11 out of 14) and was typically associated with widespread loss of heterozygosity (LOH), but was not required for progression to late-stage disease. Furthermore, tumor mutational signatures were consistent with melanoma subtype and chemotherapy exposure. Both monoclonal and polyclonal metastatic seeding were observed in the cohort. Interestingly, brain metastases were found to differ from metastases to other sites. Although brain metastases emerge late in disease progression, they were found to contain clones that had diverged early during clonal evolution, which indicates a period of dormancy upon metastatic seeding into the brain. Acquisition of resistance to therapies was also analyzed: lack of response to ICIs was associated with loss of genes linked to antigen-presentation pathways (such as B2M and JAK2) and with amplification of MYC and gain of 1q, whereas analysis of nonsynonymous mutations revealed no skewing towards neoantigen loss. Resistance to targeted therapies was associated with secondary driver mutations in MAPK pathway genes. Analysis of a KIT-driven melanoma showed that extrachromosomal DNA might contribute to the resistance to KIT inhibitors. This multilesional multiomics study expands our understanding of the mechanisms of metastasis and treatment resistance in advanced melanoma.
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