{"entity":{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","aka":["KEGG hsa05212","Pancreatic cancer"],"tldr":"This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.","summary":"Infiltrating ductal adenocarcinoma is the most common pancreatic malignancy and progresses from normal duct epithelium through histologically defined precursors (PanINs). KEGG map hsa05212 draws the sequence: HER2 (ERBB2) over-expression and activating KRAS point mutation occur early, inactivation of p16 (CDKN2A) at an intermediate stage, and inactivation of TP53, SMAD4 and BRCA2 relatively late. Activated KRAS engages several effector arms at once: RAF-MEK-ERK, PI3K-AKT and RalGDS. EGFR family receptors sit both upstream of RAS and downstream of it, because RAS induces autocrine EGFR ligands; HER2 also feeds JAK-STAT. Loss of p16 releases CDK4/6 and the G1/S checkpoint; loss of TP53 removes damage-induced arrest; loss of SMAD4 removes the growth-inhibitory arm of TGF-beta signalling. The tumours show extensive genomic instability and aneuploidy, to which telomere attrition and TP53 and BRCA2 mutation contribute.\n\nKleeff and colleagues, Nature Reviews Disease Primers, 2016 (doi:10.1038/nrdp.2016.22) review the disease: KRAS mutation is found in more than 90 percent of tumours, CDKN2A, TP53 and SMAD4 are the other frequently altered drivers, a dense stroma limits drug delivery, and germline BRCA1/2 and other homologous recombination defects define a subset that responds to platinum and PARP inhibition.\n\nWhat drugs do about it: direct KRAS inhibition has arrived, with KRAS G12C inhibitors (sotorasib, adagrasib) for the small G12C subset and the pan-RAS(ON) inhibitor daraxonrasib in phase 3 for the common G12D and G12V mutations; olaparib maintenance treats germline BRCA-mutant disease after platinum; erlotinib with gemcitabine (listed by KEGG) gives a small EGFR-directed benefit; larotrectinib and entrectinib treat rare NTRK fusion tumours; pembrolizumab treats the rare MSI-high tumours. Cytotoxic chemotherapy (FOLFIRINOX, gemcitabine with nab-paclitaxel) remains the backbone.","asOf":"2026-09-10","links":[{"label":"KEGG map hsa05212","url":"https://www.kegg.jp/pathway/hsa05212"},{"label":"Review: Pancreatic cancer (Nature Reviews Disease Primers)","url":"https://doi.org/10.1038/nrdp.2016.22"}],"tags":[],"related":["ras-mapk","ddr","tgf-beta"],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":["her2","kras","braf","pik3ca","jak2","cdk4-6","tp53","brca","egfr","ntrk","parp"],"drugs":["sotorasib","adagrasib","daraxonrasib","olaparib","erlotinib","gemcitabine","folfirinox","larotrectinib","entrectinib","pembrolizumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor","p53-cell-cycle","tgf-beta","ddr","jak-stat","rtk-activation"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kleeff-nat-rev-dis-primers"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A locked room escape in reverse. KRAS mutation is the first lock picked, and it opens three doors at once (ERK, PI3K, RalGDS). p16, TP53 and SMAD4 are guards posted at later doors, removed one by one. The room is also surrounded by a thick wall of scar-like stroma that keeps rescuers (drugs) out.","nodes":[{"id":"her2","label":"HER2 / EGFR (early)","x":50,"y":5,"targetId":"her2"},{"id":"kras","label":"KRAS mutation (early)","x":50,"y":24,"targetId":"kras"},{"id":"erk","label":"RAF / MEK / ERK","x":20,"y":44,"targetId":"braf"},{"id":"pi3k","label":"PI3K / AKT","x":50,"y":44,"targetId":"pik3ca"},{"id":"ral","label":"RalGDS","x":80,"y":44},{"id":"jak","label":"JAK / STAT","x":92,"y":24,"targetId":"jak2"},{"id":"p16","label":"p16 / CDK4-6 (intermediate)","x":15,"y":66,"targetId":"cdk4-6"},{"id":"p53","label":"TP53 (late)","x":45,"y":66,"targetId":"tp53"},{"id":"smad4","label":"SMAD4 / TGF-beta (late)","x":70,"y":66},{"id":"brca2","label":"BRCA2 (late)","x":92,"y":66,"targetId":"brca"},{"id":"out","label":"PanIN to ductal adenocarcinoma","x":50,"y":94}],"edges":[{"from":"her2","to":"kras","type":"activates"},{"from":"kras","to":"her2","type":"activates"},{"from":"her2","to":"jak","type":"activates"},{"from":"kras","to":"erk","type":"activates"},{"from":"kras","to":"pi3k","type":"activates"},{"from":"kras","to":"ral","type":"activates"},{"from":"erk","to":"out","type":"activates"},{"from":"pi3k","to":"out","type":"activates"},{"from":"ral","to":"out","type":"activates"},{"from":"jak","to":"out","type":"activates"},{"from":"p16","to":"out","type":"inhibits"},{"from":"p53","to":"out","type":"inhibits"},{"from":"smad4","to":"out","type":"inhibits"},{"from":"brca2","to":"out","type":"inhibits"}],"interventions":["Direct KRAS inhibition: sotorasib or adagrasib for KRAS G12C; pan-RAS(ON) inhibitor daraxonrasib in phase 3 for G12D/G12V disease","PARP inhibitor olaparib as maintenance for germline BRCA-mutant tumours after platinum chemotherapy","EGFR inhibitor erlotinib with gemcitabine (small benefit, listed by KEGG)","NTRK fusion tumours: larotrectinib, entrectinib; MSI-high tumours: pembrolizumab","Chemotherapy backbone: FOLFIRINOX or gemcitabine with nab-paclitaxel"]},"route":"/pathways/pancreatic-cancer-signalling/","neighbours":{"pathway":[{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"jak-stat","kind":"pathway","name":"JAK-STAT signalling","route":"/pathways/jak-stat/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"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/"}],"cancer":[{"id":"pancreatic-adenosquamous-carcinoma","kind":"cancer","name":"Adenosquamous carcinoma of the pancreas","route":"/cancers/pancreatic-adenosquamous-carcinoma/"},{"id":"borderline-resectable-pdac","kind":"cancer","name":"Borderline resectable pancreatic ductal adenocarcinoma","route":"/cancers/borderline-resectable-pdac/"},{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","route":"/cancers/brca-palb2-pdac/"},{"id":"pancreatic-colloid-carcinoma","kind":"cancer","name":"Colloid (mucinous non-cystic) carcinoma of the pancreas","route":"/cancers/pancreatic-colloid-carcinoma/"},{"id":"ipmn-cystic-precursors","kind":"cancer","name":"Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors","route":"/cancers/ipmn-cystic-precursors/"},{"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-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":"locally-advanced-pdac","kind":"cancer","name":"Locally advanced unresectable pancreatic ductal adenocarcinoma","route":"/cancers/locally-advanced-pdac/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"mcn-associated-carcinoma","kind":"cancer","name":"Mucinous cystic neoplasm of the pancreas with associated invasive carcinoma (MCN-associated carcinoma)","route":"/cancers/mcn-associated-carcinoma/"},{"id":"pancreatic-acinar-cell-carcinoma","kind":"cancer","name":"Pancreatic acinar cell carcinoma","route":"/cancers/pancreatic-acinar-cell-carcinoma/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"pancreatoblastoma","kind":"cancer","name":"Pancreatoblastoma","route":"/cancers/pancreatoblastoma/"},{"id":"resectable-pdac","kind":"cancer","name":"Resectable pancreatic ductal adenocarcinoma","route":"/cancers/resectable-pdac/"},{"id":"solid-pseudopapillary-neoplasm","kind":"cancer","name":"Solid pseudopapillary neoplasm of the pancreas","route":"/cancers/solid-pseudopapillary-neoplasm/"},{"id":"pancreatic-undifferentiated-carcinoma-ogc","kind":"cancer","name":"Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells","route":"/cancers/pancreatic-undifferentiated-carcinoma-ogc/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"jak2","kind":"target","name":"JAK2","route":"/targets/jak2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"ntrk","kind":"target","name":"NTRK","route":"/targets/ntrk/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"entrectinib","kind":"drug","name":"Entrectinib","route":"/drugs/entrectinib/"},{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"},{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/"},{"id":"gemcitabine","kind":"drug","name":"Gemcitabine","route":"/drugs/gemcitabine/"},{"id":"larotrectinib","kind":"drug","name":"Larotrectinib","route":"/drugs/larotrectinib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"paper":[{"id":"paper-jones-pancreatic-core-pathways-science-2008","kind":"paper","name":"Core signaling pathways in human pancreatic cancers revealed by global genomic analyses","route":"/key-papers/paper-jones-pancreatic-core-pathways-science-2008/"},{"id":"paper-bailey-molecular-subtypes-pancreatic-nature-2016","kind":"paper","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/"},{"id":"paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017","kind":"paper","name":"Integrated genomic characterization of pancreatic ductal adenocarcinoma","route":"/key-papers/paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017/"},{"id":"paper-kleeff-nat-rev-dis-primers","kind":"paper","name":"Pancreatic cancer","route":"/key-papers/paper-kleeff-nat-rev-dis-primers/"},{"id":"paper-biankin-pancreatic-exomes-axon-guidance-nature-2012","kind":"paper","name":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","route":"/key-papers/paper-biankin-pancreatic-exomes-axon-guidance-nature-2012/"}],"term":[{"id":"classical-vs-basal-like","kind":"term","name":"Classical versus basal-like (squamous) subtypes of pancreatic cancer, and GATA6","route":"/terms/classical-vs-basal-like/"}]}}