KEGG PATHWAY: hsa05212

PATHWAY: hsa05212

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; Cancer: specific types

Pathway map

hsa05212

Pancreatic cancer

Network

Element

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; component of inhibitor of nuclear factor kappa B kinase complex [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 regulatory 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]

5337	PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]

5338	PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]

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:K23605]

4089	SMAD4; SMAD family member 4 [KO:K04501]

675	BRCA2; BRCA2 DNA repair associated [KO:K08775]

5888	RAD51; RAD51 recombinase [KO:K04482]

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

Authors

Niitsu Y, Yokota J (ed).

Title

[Oncogenes and Tumor Suppressor Genes for Medical Oncologist] (In Japanese)

Journal

Nankodo (1999)

Reference

PMID:12459728

Authors

Bardeesy N, DePinho RA.

Title

Pancreatic cancer biology and genetics.

Journal

Nat Rev Cancer 2:897-909 (2002)
DOI:10.1038/nrc949

Reference

PMID:11407945

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

PMID:12946833

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

PMID:16702400

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

PMID:10740269

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

PMID:12648469

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

PMID:14967450

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

PMID:14586404

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

PMID:12545153

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

PMID:14580692

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

PMID:12079267

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

PMID:15774796