{"entity":{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","aka":[],"tldr":"The RAS-MAPK pathway is the cell's 'divide' relay. A signal at the surface flips RAS on, which passes to RAF, MEK, and ERK, which tell the nucleus to make the cell divide. KRAS and BRAF mutations jam it in the on position.","summary":"Growth-factor receptors recruit GRB2/SOS to load GTP onto RAS (KRAS, NRAS, HRAS). RAS-GTP recruits RAF (BRAF, CRAF) dimers, which phosphorylate MEK1/2, which phosphorylate ERK1/2. ERK drives transcription of cyclin D1, MYC, and negative feedback (DUSP, SPRY). Alterations: KRAS (pancreatic 90%, CRC 45%, lung 30%), BRAF V600E (melanoma 50%), NF1 loss, receptor fusions (ALK, RET, NTRK). Drugs: KRAS G12C inhibitors, pan-RAS(ON) inhibitors, BRAF+MEK doublets, upstream RTK inhibitors. Feedback reactivation (loss of ERK-mediated inhibition of RTKs) is why single agents fail and vertical combinations (BRAF+MEK, KRAS+EGFR in CRC) work.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/MAPK/ERK_pathway","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/MAPK/ERK_pathway"}],"tags":[],"related":[],"cancers":["pancreatic","colorectal","nsclc","melanoma","gallbladder"],"sections":[],"technologies":[],"targets":["kras","braf","egfr","alk","ret","met","ntrk","fgfr2","kit","nras","shp2","nf1"],"drugs":["sotorasib","adagrasib","daraxonrasib","encorafenib","osimertinib","lorlatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"analogy":"A relay race: receptor hands the baton to RAS, RAS to RAF, RAF to MEK, MEK to ERK, ERK runs into the nucleus and shouts 'divide'. A KRAS mutation is a runner who never stops running whether or not anyone handed them the baton.","nodes":[{"id":"rtk","label":"RTK (EGFR, ALK, RET, MET)","x":50,"y":5,"targetId":"egfr"},{"id":"sos","label":"GRB2 / SOS1","x":50,"y":20},{"id":"ras","label":"RAS (KRAS)","x":50,"y":36,"targetId":"kras"},{"id":"nf1","label":"NF1 (GAP)","x":15,"y":36},{"id":"raf","label":"RAF (BRAF)","x":50,"y":52,"targetId":"braf"},{"id":"mek","label":"MEK1/2","x":50,"y":68},{"id":"erk","label":"ERK1/2","x":50,"y":82},{"id":"out","label":"Cyclin D1, MYC → proliferation","x":50,"y":97},{"id":"fb","label":"DUSP / SPRY feedback","x":85,"y":60}],"edges":[{"from":"rtk","to":"sos","type":"activates"},{"from":"sos","to":"ras","type":"activates"},{"from":"nf1","to":"ras","type":"inhibits"},{"from":"ras","to":"raf","type":"activates"},{"from":"raf","to":"mek","type":"activates"},{"from":"mek","to":"erk","type":"activates"},{"from":"erk","to":"out","type":"activates"},{"from":"erk","to":"fb","type":"activates"},{"from":"fb","to":"rtk","type":"inhibits"}],"interventions":["KRAS G12C inhibitors (sotorasib, adagrasib) ± anti-EGFR in colorectal cancer","Pan-RAS(ON) inhibitor daraxonrasib (phase 3, pancreatic)","BRAF + MEK inhibitors (dabrafenib/trametinib, encorafenib/binimetinib)","Encorafenib + cetuximab (+ chemo) in BRAF V600E CRC","Upstream: EGFR, ALK, RET, MET, NTRK inhibitors and bispecifics"]},"route":"/pathways/ras-mapk/","neighbours":{"cancer":[{"id":"acral-melanoma","kind":"cancer","name":"Acral 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V600E-mutant non-small-cell lung cancer","route":"/cancers/braf-v600e-nsclc/"},{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"id":"pancreatic-colloid-carcinoma","kind":"cancer","name":"Colloid (mucinous non-cystic) carcinoma of the pancreas","route":"/cancers/pancreatic-colloid-carcinoma/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"craniopharyngioma","kind":"cancer","name":"Craniopharyngioma","route":"/cancers/craniopharyngioma/"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"erdheim-chester-disease","kind":"cancer","name":"Erdheim-Chester disease","route":"/cancers/erdheim-chester-disease/"},{"id":"histiocytoses","kind":"cancer","name":"Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms","route":"/cancers/histiocytoses/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"gist","kind":"cancer","name":"Gastrointestinal stromal tumour (GIST)","route":"/cancers/gist/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"hairy-cell-leukemia","kind":"cancer","name":"Hairy cell leukaemia","route":"/cancers/hairy-cell-leukemia/"},{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","route":"/cancers/her2-amplified-colorectal/"},{"id":"breast-her2-positive","kind":"cancer","name":"HER2-positive breast cancer","route":"/cancers/breast-her2-positive/"},{"id":"inflammatory-myofibroblastic-tumour","kind":"cancer","name":"Inflammatory myofibroblastic tumour (IMT)","route":"/cancers/inflammatory-myofibroblastic-tumour/"},{"id":"ipmn-associated-carcinoma","kind":"cancer","name":"Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma)","route":"/cancers/ipmn-associated-carcinoma/"},{"id":"kras-g12c-colorectal","kind":"cancer","name":"KRAS G12C-mutant colorectal cancer","route":"/cancers/kras-g12c-colorectal/"},{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"},{"id":"kras-g12c-pdac","kind":"cancer","name":"KRAS G12C-mutant pancreatic ductal adenocarcinoma","route":"/cancers/kras-g12c-pdac/"},{"id":"kras-wild-type-pdac","kind":"cancer","name":"KRAS wild-type pancreatic ductal adenocarcinoma","route":"/cancers/kras-wild-type-pdac/"},{"id":"langerhans-cell-histiocytosis","kind":"cancer","name":"Langerhans cell histiocytosis 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