KEGG   PATHWAY: hsa05212Help
Entry
hsa05212                    Pathway                                

Name
Pancreatic cancer - Homo sapiens (human)
Description
Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways.  Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.
Class
Human Diseases; Cancers
BRITE hierarchy
Pathway map
hsa05212  Pancreatic cancer
hsa05212

Ortholog table
Network
N00012  Mutation-activated KRAS/NRAS to ERK signaling pathway
N00032  Mutation-activated KRAS/NRAS to PI3K signaling pathway
N00034  ERBB2-overexpression to PI3K signaling pathway
N00070  Mutation-inactivated p16(INK4a) to p16-cell cycle G1/S
N00071  Deleted p16(INK4a) to p16-cell cycle G1/S
N00095  ERBB2-overexpression to EGF-Jak-STAT signaling pathway
N00104  Mutation-activated KRAS to RalGDS signaling pathway
N00115  Mutation-inactivated TP53 to transcription
Disease
H00019  Pancreatic cancer
Drug
D04023  Erlotinib hydrochloride (JAN/USAN)
D07907  Erlotinib (INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
9459  ARHGEF6; Rac/Cdc42 guanine nucleotide exchange factor 6 [KO:K05729]
5879  RAC1; Rac family small GTPase 1 [KO:K04392]
5880  RAC2; Rac family small GTPase 2 [KO:K07860]
5881  RAC3; Rac family small GTPase 3 [KO:K07861]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
1147  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
572  BAD; BCL2 associated agonist of cell death [KO:K02158]
598  BCL2L1; BCL2 like 1 [KO:K04570]
842  CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
369  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
5900  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
5898  RALA; RAS like proto-oncogene A [KO:K07834]
5899  RALB; RAS like proto-oncogene B [KO:K07835]
10928  RALBP1; ralA binding protein 1 [KO:K08773]
998  CDC42; cell division cycle 42 [KO:K04393]
7039  TGFA; transforming growth factor alpha [KO:K08774]
1950  EGF; epidermal growth factor [KO:K04357]
1956  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
2064  ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
3716  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
7422  VEGFA; vascular endothelial growth factor A [KO:K05448]
1029  CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621]
1019  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
1021  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
595  CCND1; cyclin D1 [KO:K04503]
5925  RB1; RB transcriptional corepressor 1 [KO:K06618]
1869  E2F1; E2F transcription factor 1 [KO:K17454]
1870  E2F2; E2F transcription factor 2 [KO:K09389]
1871  E2F3; E2F transcription factor 3 [KO:K06620]
7157  TP53; tumor protein p53 [KO:K04451]
1026  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
1647  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
4616  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
10912  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
581  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
578  BAK1; BCL2 antagonist/killer 1 [KO:K14021]
1643  DDB2; damage specific DNA binding protein 2 [KO:K10140]
51426  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
7040  TGFB1; transforming growth factor beta 1 [KO:K13375]
7042  TGFB2; transforming growth factor beta 2 [KO:K13376]
7043  TGFB3; transforming growth factor beta 3 [KO:K13377]
7046  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
7048  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
4087  SMAD2; SMAD family member 2 [KO:K04500]
4088  SMAD3; SMAD family member 3 [KO:K04500]
4089  SMAD4; SMAD family member 4 [KO:K04501]
675  BRCA2; BRCA2, DNA repair associated [KO:K08775]
5888  RAD51; RAD51 recombinase [KO:K04482]
5337  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
Compound
C00416  Phosphatidate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Von Hoff D, Evans D, Hruban R (ed).
  Title
Pancreatic cancer
  Journal
Jones and Bartlett publishers (2005)
Reference
(Japanese)
  Authors
Niitsu Y, Yokota J (ed).
  Title
[Oncogenes and Tumor Suppressor Genes for Medical Oncologist] (In Japanese)
  Journal
Nankodo (1999)
Reference
  Authors
Bardeesy N, DePinho RA.
  Title
Pancreatic cancer biology and genetics.
  Journal
Nat Rev Cancer 2:897-909 (2002)
DOI:10.1038/nrc949
Reference
  Authors
Bardeesy N, Sharpless NE, DePinho RA, Merlino G.
  Title
The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model.
  Journal
Semin Cancer Biol 11:201-18 (2001)
DOI:10.1006/scbi.2000.0371
Reference
  Authors
Cowgill SM, Muscarella P.
  Title
The genetics of pancreatic cancer.
  Journal
Am J Surg 186:279-86 (2003)
DOI:10.1016/S0002-9610(03)00226-5
Reference
  Authors
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA.
  Title
Genetics and biology of pancreatic ductal adenocarcinoma.
  Journal
Genes Dev 20:1218-49 (2006)
DOI:10.1101/gad.1415606
Reference
  Authors
Shields JM, Pruitt K, McFall A, Shaub A, Der CJ.
  Title
Understanding Ras: 'it ain't over 'til it's over'.
  Journal
Trends Cell Biol 10:147-54 (2000)
DOI:10.1016/S0962-8924(00)01740-2
Reference
  Authors
Holbro T, Civenni G, Hynes NE.
  Title
The ErbB receptors and their role in cancer progression.
  Journal
Exp Cell Res 284:99-110 (2003)
DOI:10.1016/S0014-4827(02)00099-X
Reference
  Authors
Marmor MD, Skaria KB, Yarden Y.
  Title
Signal transduction and oncogenesis by ErbB/HER receptors.
  Journal
Int J Radiat Oncol Biol Phys 58:903-13 (2004)
DOI:10.1016/j.ijrobp.2003.06.002
Reference
  Authors
DeArmond D, Brattain MG, Jessup JM, Kreisberg J, Malik S, Zhao S, Freeman JW.
  Title
Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines.
  Journal
Oncogene 22:7781-95 (2003)
DOI:10.1038/sj.onc.1206966
Reference
  Authors
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K.
  Title
Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.
  Journal
Oncogene 22:319-29 (2003)
DOI:10.1038/sj.onc.1206122
Reference
  Authors
Toyonaga T, Nakano K, Nagano M, Zhao G, Yamaguchi K, Kuroki S, Eguchi T, Chijiiwa K, Tsuneyoshi M, Tanaka M.
  Title
Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer.
  Journal
Cancer Lett 201:107-16 (2003)
DOI:10.1016/S0304-3835(03)00482-8
Reference
  Authors
Schmid RM.
  Title
Genetic basis of pancreatic cancer.
  Journal
Best Pract Res Clin Gastroenterol 16:421-33 (2002)
DOI:10.1053/bega.2002.0316
Reference
  Authors
Elliott RL, Blobe GC.
  Title
Role of transforming growth factor Beta in human cancer.
  Journal
J Clin Oncol 23:2078-93 (2005)
DOI:10.1200/JCO.2005.02.047
Reference
  Authors
Rudkin TM, Foulkes WD.
  Title
BRCA2: breaks, mistakes and failed separations.
  Journal
Trends Mol Med 11:145-8 (2005)
DOI:10.1016/j.molmed.2005.02.003
Reference
  Authors
Venkitaraman AR.
  Title
Functions of BRCA1 and BRCA2 in the biological response to DNA damage.
  Journal
J Cell Sci 114:3591-8 (2001)
Reference
  Authors
Chang Z, Li Z, Wang X, Kang Y, Yuan Y, Niu J, Wang H, Chatterjee D, Fleming JB, Li M, Abbruzzese JL, Chiao PJ
  Title
Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.
  Journal
Clin Cancer Res 19:549-59 (2013)
DOI:10.1158/1078-0432.CCR-12-0032
KO pathway
ko05212   

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