{"entity":{"id":"gastric-cancer-signalling","kind":"pathway","name":"Gastric cancer (KEGG map)","aka":["KEGG hsa05226","Gastric cancer"],"tldr":"This KEGG map splits stomach cancer into two routes: the intestinal type that accumulates TP53, APC and HER2 changes step by step, and the diffuse type driven by loss of the cell glue E-cadherin plus MET or FGFR2 amplification. It matters because HER2, FGFR2, claudin 18.2 and PD-1 status now decide first-line treatment.","summary":"Gastric cancer is one of the most common cancers worldwide and is divided by the Lauren classification into intestinal and diffuse types. KEGG map hsa05226 draws the intestinal-type sequence: intestinal metaplasia carries TP53 mutation, reduced retinoic acid receptor beta and hTERT expression; gastric adenomas add APC mutation, reduced p27 (CDKN1B) and cyclin E amplification; advanced tumours show ERBB2 (HER2) amplification, reduced TGF-beta receptor I and complete loss of p27. Amplified HER2, FGFR2 and MET all feed RAS-ERK and PI3K-AKT; CDX2 over-expression alters transcription. The diffuse type is defined by loss of E-cadherin through CDH1 mutation (germline in hereditary diffuse gastric cancer), which releases beta-catenin, and by MET and FGFR2 amplification.\n\nSmyth and colleagues, The Lancet, 2020 (doi:10.1016/S0140-6736(20)31288-5) review the disease: Helicobacter pylori is the main cause, The Cancer Genome Atlas separates EBV-positive, MSI, genomically stable (diffuse, CDH1 and RHOA altered) and chromosomally unstable (intestinal, receptor amplified) subtypes, and biomarker testing for HER2, PD-L1 and MSI guides therapy.\n\nWhat drugs do about it: trastuzumab plus chemotherapy, now with pembrolizumab, is standard for HER2-positive disease, with trastuzumab deruxtecan and zanidatamab after progression; nivolumab or pembrolizumab with chemotherapy treats HER2-negative disease with PD-L1 expression; zolbetuximab treats claudin 18.2-positive tumours; ramucirumab blocks VEGFR2 in second line; the FGFR2b antibody bemarituzumab is in phase 3 for FGFR2b over-expressing tumours; MSI-high tumours respond to checkpoint inhibitors. The CDH1/E-cadherin loss that defines diffuse cancer has no direct drug.","asOf":"2026-09-10","links":[{"label":"KEGG map hsa05226","url":"https://www.kegg.jp/pathway/hsa05226"},{"label":"Review: Gastric cancer (Lancet seminar)","url":"https://doi.org/10.1016/S0140-6736(20)31288-5"}],"tags":[],"related":["rtk-activation","fgfr-signalling","emt","pd1-checkpoint"],"cancers":["gastric"],"sections":[],"technologies":[],"targets":["tp53","her2","fgfr2","met","kras","pik3ca","cldn18-2","pd1","vegf"],"drugs":["trastuzumab","pembrolizumab","trastuzumab-deruxtecan","zanidatamab","nivolumab","zolbetuximab","bemarituzumab","ramucirumab","paclitaxel"],"companies":[],"institutions":[],"pathways":["rtk-activation","fgfr-signalling","ras-mapk","pi3k-akt-mtor","p53-cell-cycle","wnt","tgf-beta","emt","pd1-checkpoint","mismatch-repair-msi"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-smyth-lancet"],"journals":[],"dependsOn":[],"notes":[],"analogy":"Two different ways a wall fails. In the intestinal type the bricks are replaced one at a time with faulty ones (TP53, APC, HER2) until the wall bows outward. In the diffuse type the mortar (E-cadherin) dissolves, so the bricks scatter and slip between other layers. The drugs mostly aim at loudspeakers bolted to the wall (HER2, FGFR2, claudin 18.2) rather than the bricks or mortar.","nodes":[{"id":"hp","label":"H. pylori, metaplasia","x":50,"y":4},{"id":"p53","label":"TP53 / hTERT","x":15,"y":22,"targetId":"tp53"},{"id":"apc","label":"APC / p27 / cyclin E","x":40,"y":22},{"id":"her2","label":"HER2 amplified","x":65,"y":22,"targetId":"her2"},{"id":"fgfr2","label":"FGFR2 / MET amplified","x":90,"y":22,"targetId":"fgfr2"},{"id":"cdh1","label":"E-cadherin (CDH1) lost","x":15,"y":50},{"id":"bcat","label":"beta-catenin","x":15,"y":72},{"id":"ras","label":"RAS / ERK","x":60,"y":50,"targetId":"kras"},{"id":"pi3k","label":"PI3K / AKT","x":85,"y":50,"targetId":"pik3ca"},{"id":"tgfb","label":"TGF-beta receptor I (reduced)","x":40,"y":50},{"id":"cldn","label":"Claudin 18.2 / PD-L1 (surface)","x":72,"y":74,"targetId":"cldn18-2"},{"id":"out","label":"Intestinal or diffuse gastric cancer","x":45,"y":94}],"edges":[{"from":"hp","to":"p53","type":"inhibits"},{"from":"hp","to":"apc","type":"activates"},{"from":"hp","to":"her2","type":"activates"},{"from":"hp","to":"fgfr2","type":"activates"},{"from":"hp","to":"cdh1","type":"inhibits"},{"from":"cdh1","to":"bcat","type":"inhibits"},{"from":"bcat","to":"out","type":"activates"},{"from":"her2","to":"ras","type":"activates"},{"from":"her2","to":"pi3k","type":"activates"},{"from":"fgfr2","to":"ras","type":"activates"},{"from":"fgfr2","to":"pi3k","type":"activates"},{"from":"ras","to":"out","type":"activates"},{"from":"pi3k","to":"out","type":"activates"},{"from":"p53","to":"out","type":"inhibits"},{"from":"apc","to":"out","type":"activates"},{"from":"tgfb","to":"out","type":"inhibits"},{"from":"cldn","to":"out","type":"activates"}],"interventions":["HER2-positive: trastuzumab plus chemotherapy and pembrolizumab first line; trastuzumab deruxtecan or zanidatamab after progression","HER2-negative, PD-L1 expressing: nivolumab or pembrolizumab with chemotherapy","Claudin 18.2-positive: zolbetuximab with chemotherapy","FGFR2b over-expressing: bemarituzumab (phase 3); MET amplified: MET inhibitors in trials","Second line: ramucirumab (VEGFR2) with paclitaxel; MSI-high: checkpoint inhibitors","E-cadherin/CDH1 loss: no direct drug yet"]},"route":"/pathways/gastric-cancer-signalling/","neighbours":{"pathway":[{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"fgfr-signalling","kind":"pathway","name":"FGF / FGFR signalling","route":"/pathways/fgfr-signalling/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"},{"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":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"cancer":[{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"cdh1","kind":"target","name":"CDH1","route":"/targets/cdh1/"},{"id":"cldn18-2","kind":"target","name":"Claudin 18.2","route":"/targets/cldn18-2/"},{"id":"fgfr2","kind":"target","name":"FGFR2","route":"/targets/fgfr2/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"bemarituzumab","kind":"drug","name":"Bemarituzumab","route":"/drugs/bemarituzumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"ramucirumab","kind":"drug","name":"Ramucirumab","route":"/drugs/ramucirumab/"},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"},{"id":"zanidatamab","kind":"drug","name":"Zanidatamab","route":"/drugs/zanidatamab/"},{"id":"zolbetuximab","kind":"drug","name":"Zolbetuximab","route":"/drugs/zolbetuximab/"}],"paper":[{"id":"paper-smyth-lancet","kind":"paper","name":"Gastric cancer","route":"/key-papers/paper-smyth-lancet/"}]}}