{"entity":{"id":"melanoma-signalling","kind":"pathway","name":"Melanoma (KEGG map)","aka":["KEGG hsa05218","Melanoma"],"tldr":"KEGG's melanoma map shows BRAF or NRAS mutations driving the MAPK growth relay, PTEN loss driving PI3K/AKT, and loss of the CDKN2A brakes (p16 and p14ARF) on CDK4/6 and p53. BRAF plus MEK inhibitors and immune checkpoint antibodies have transformed treatment.","summary":"The KEGG melanoma map (hsa05218) traces how melanocytes become melanoma. Growth factor receptors and, far more often, mutations in BRAF (mostly V600E) or NRAS lock on the RAF to MEK to ERK relay, which drives cyclin D1 and proliferation. NRAS also feeds PI3K, and loss or mutation of PTEN releases AKT signalling for survival. These mutations arise early, in the benign naevus stage, and persist. Progression is then tied to the two tumour suppressor arms drawn on the map: p16INK4a normally holds CDK4/6 away from cyclin D so RB stays bound to E2F, and p14ARF normally blocks MDM2 so that p53 is stable; deletion or mutation of the CDKN2A locus, or activating CDK4 mutation, removes both brakes at once. MITF, the melanocyte master transcription factor, and TP53 mutations are implicated in further progression. Shain and Bastian, Nat Rev Cancer, 2016 (doi:10.1038/nrc.2016.37) review the genetic evolution from melanocyte to melanoma, showing MAPK activation as the initiating event, CDKN2A loss and telomerase promoter mutations at the transition to invasive melanoma, and PTEN and TP53 alterations later, on a background of ultraviolet-signature mutations.\n\nWhat drugs do about it: BRAF inhibitors paired with MEK inhibitors (dabrafenib with trametinib, vemurafenib with cobimetinib, encorafenib with binimetinib) shut the MAPK relay in BRAF V600-mutant melanoma. Immune checkpoint antibodies against PD-1 (nivolumab, pembrolizumab) with or without CTLA-4 (ipilimumab) or LAG-3 (relatlimab) produce durable remissions regardless of mutation and are now first choice for most patients with advanced disease.","asOf":"2026-09-10","links":[{"label":"KEGG map hsa05218","url":"https://www.kegg.jp/pathway/hsa05218"},{"label":"Review: From melanocytes to melanomas","url":"https://doi.org/10.1038/nrc.2016.37"}],"tags":[],"related":["ras-mapk","pd1-checkpoint"],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":["braf","mek","akt","cdk4-6","mdm2"],"drugs":["dabrafenib","trametinib","vemurafenib","cobimetinib","encorafenib","binimetinib","nivolumab","pembrolizumab","ipilimumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor","p53-cell-cycle","cell-cycle-engine-cdks","pd1-checkpoint"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-shain-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A car with the accelerator taped down (BRAF or NRAS) and both brake cables cut (p16 and p14ARF). BRAF and MEK inhibitors peel off the tape; immunotherapy calls in the police to stop the car from outside.","nodes":[{"id":"rtk","label":"Growth factor RTKs","x":50,"y":5},{"id":"nras","label":"NRAS","x":50,"y":20},{"id":"braf","label":"BRAF V600E","x":25,"y":36,"targetId":"braf"},{"id":"mek","label":"MEK / ERK","x":25,"y":54,"targetId":"mek"},{"id":"pten","label":"PTEN (lost)","x":90,"y":30},{"id":"pi3k","label":"PI3K / AKT","x":72,"y":46,"targetId":"akt"},{"id":"cdkn2a","label":"CDKN2A: p16 and p14ARF","x":50,"y":62},{"id":"cdk46","label":"Cyclin D / CDK4/6 to RB","x":30,"y":78,"targetId":"cdk4-6"},{"id":"mdm2","label":"MDM2 to p53","x":72,"y":78,"targetId":"mdm2"},{"id":"mitf","label":"MITF","x":90,"y":62},{"id":"out","label":"Proliferation, survival","x":50,"y":95}],"edges":[{"from":"rtk","to":"nras","type":"activates"},{"from":"nras","to":"braf","type":"activates"},{"from":"braf","to":"mek","type":"activates"},{"from":"nras","to":"pi3k","type":"activates"},{"from":"pten","to":"pi3k","type":"inhibits"},{"from":"mek","to":"cdk46","type":"activates"},{"from":"cdkn2a","to":"cdk46","type":"inhibits"},{"from":"cdkn2a","to":"mdm2","type":"inhibits"},{"from":"cdk46","to":"out","type":"activates"},{"from":"mdm2","to":"out","type":"activates"},{"from":"pi3k","to":"out","type":"activates"},{"from":"mitf","to":"out","type":"activates"}],"interventions":["BRAF plus MEK inhibitor doublets for BRAF V600-mutant melanoma: dabrafenib with trametinib, vemurafenib with cobimetinib, encorafenib with binimetinib","PD-1 checkpoint antibodies nivolumab or pembrolizumab, alone or combined with ipilimumab (CTLA-4) or relatlimab (LAG-3), for advanced disease and as adjuvant therapy","Adjuvant BRAF plus MEK inhibition or anti-PD-1 after resection of stage III melanoma","MEK inhibitors and CDK4/6 inhibitor combinations under study for NRAS-mutant melanoma"]},"route":"/pathways/melanoma-signalling/","neighbours":{"pathway":[{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/"}],"cancer":[{"id":"braf-v600-melanoma","kind":"cancer","name":"BRAF V600-mutant melanoma","route":"/cancers/braf-v600-melanoma/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"}],"target":[{"id":"akt","kind":"target","name":"AKT","route":"/targets/akt/"},{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"mdm2","kind":"target","name":"MDM2","route":"/targets/mdm2/"},{"id":"mek","kind":"target","name":"MEK1/2","route":"/targets/mek/"},{"id":"mitf","kind":"target","name":"MITF","route":"/targets/mitf/"},{"id":"nras","kind":"target","name":"NRAS","route":"/targets/nras/"}],"drug":[{"id":"binimetinib","kind":"drug","name":"Binimetinib","route":"/drugs/binimetinib/"},{"id":"cobimetinib","kind":"drug","name":"Cobimetinib","route":"/drugs/cobimetinib/"},{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"},{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"}],"paper":[{"id":"paper-shain-nat-rev-cancer","kind":"paper","name":"From melanocytes to melanomas","route":"/key-papers/paper-shain-nat-rev-cancer/"}]}}