KEGG   PATHWAY: mmu05223Help
Entry
mmu05223                    Pathway                                

Name
Non-small cell lung cancer - Mus musculus (mouse)
Description
Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS, EGFR and EML4-ALK, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Mutations or overexpression of EGFR leads to a proliferative advantage. EML4-ALK fusion leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a  inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC. RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.
Class
Human Diseases; Cancers
BRITE hierarchy
Pathway map
Non-small cell lung cancer
mmu05223

All organismsOrtholog table
Organism
Mus musculus (mouse) [GN:mmu]
Gene
14198  
Fhit; fragile histidine triad gene [KO:K01522] [EC:3.6.1.29]
218772  
Rarb; retinoic acid receptor, beta [KO:K08528]
20181  
Rxra; retinoid X receptor alpha [KO:K08524]
20182  
Rxrb; retinoid X receptor beta [KO:K08525]
20183  
Rxrg; retinoid X receptor gamma [KO:K08526]
12578  
Cdkn2a; cyclin-dependent kinase inhibitor 2A [KO:K06621]
12567  
Cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
12571  
Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
12443  
Ccnd1; cyclin D1 [KO:K04503]
19645  
Rb1; RB transcriptional corepressor 1 [KO:K06618]
13555  
E2f1; E2F transcription factor 1 [KO:K17454]
242705  
E2f2; E2F transcription factor 2 [KO:K09389]
13557  
E2f3; E2F transcription factor 3 [KO:K06620]
16653  
Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
56289  
Rassf1; Ras association (RalGDS/AF-6) domain family member 1 [KO:K09850]
54354  
Rassf5; Ras association (RalGDS/AF-6) domain family member 5 [KO:K08015]
58231  
Stk4; serine/threonine kinase 4 [KO:K04411]
18706  
Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  
Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
74769  
Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
18709  
Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  
Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  
Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
18607  
Pdpk1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
11651  
Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]
11652  
Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]
23797  
Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]
12015  
Bad; BCL2-associated agonist of cell death [KO:K02158]
12371  
Casp9; caspase 9 [KO:K04399] [EC:3.4.22.62]
56484  
Foxo3; forkhead box O3 [KO:K09408]
13645  
Egf; epidermal growth factor [KO:K04357]
21802  
Tgfa; transforming growth factor alpha [KO:K08774]
13649  
Egfr; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
13866  
Erbb2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
14784  
Grb2; growth factor receptor bound protein 2 [KO:K04364]
20662  
Sos1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
20663  
Sos2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
15461  
Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
18176  
Nras; neuroblastoma ras oncogene [KO:K07828]
11836  
Araf; Araf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
109880  
Braf; Braf transforming gene [KO:K04365] [EC:2.7.11.1]
110157  
Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:2.7.11.1]
26395  
Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
26396  
Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
26413  
Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  
Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
18803  
Plcg1; phospholipase C, gamma 1 [KO:K01116] [EC:3.1.4.11]
234779  
Plcg2; phospholipase C, gamma 2 [KO:K05859] [EC:3.1.4.11]
18750  
Prkca; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
18751  
Prkcb; protein kinase C, beta [KO:K19662] [EC:2.7.11.13]
18752  
Prkcg; protein kinase C, gamma [KO:K19663] [EC:2.7.11.13]
22059  
Trp53; transformation related protein 53 [KO:K04451]
12575  
Cdkn1a; cyclin-dependent kinase inhibitor 1A (P21) [KO:K06625]
13197  
Gadd45a; growth arrest and DNA-damage-inducible 45 alpha [KO:K04402]
17873  
Gadd45b; growth arrest and DNA-damage-inducible 45 beta [KO:K04402]
23882  
Gadd45g; growth arrest and DNA-damage-inducible 45 gamma [KO:K04402]
12028  
Bax; BCL2-associated X protein [KO:K02159]
12018  
Bak1; BCL2-antagonist/killer 1 [KO:K14021]
107986  
Ddb2; damage specific DNA binding protein 2 [KO:K10140]
27015  
Polk; polymerase (DNA directed), kappa [KO:K03511] [EC:2.7.7.7]
78798  
Eml4; echinoderm microtubule associated protein like 4 [KO:K15420]
11682  
Alk; anaplastic lymphoma kinase [KO:K05119] [EC:2.7.10.1]
16453  
Jak3; Janus kinase 3 [KO:K11218] [EC:2.7.10.2]
20848  
Stat3; signal transducer and activator of transcription 3 [KO:K04692]
20850  
Stat5a; signal transducer and activator of transcription 5A [KO:K11223]
20851  
Stat5b; signal transducer and activator of transcription 5B [KO:K11224]
Compound
C00076  
Calcium cation
C00165  
Diacylglycerol
C00777  
Retinoate
C01245  
D-myo-Inositol 1,4,5-trisphosphate
C05981  
Phosphatidylinositol-3,4,5-trisphosphate
C15493  
9-cis-Retinoic acid
Reference
  Authors
Osada H, Takahashi T.
  Title
Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer.
  Journal
Oncogene 21:7421-34 (2002)
DOI:10.1038/sj.onc.1205802
Reference
  Authors
Yokota J, Nishioka M, Tani M, Kohno T.
  Title
Genetic alterations responsible for metastatic phenotypes of lung cancer cells.
  Journal
Clin Exp Metastasis 20:189-93 (2003)
Reference
  Authors
Aviel-Ronen S, Blackhall FH, Shepherd FA, Tsao MS.
  Title
K-ras mutations in non-small-cell lung carcinoma: a review.
  Journal
Clin Lung Cancer 8:30-8 (2006)
DOI:10.3816/CLC.2006.n.030
Reference
  Authors
Pfeifer GP, Dammann R.
  Title
Methylation of the tumor suppressor gene RASSF1A in human tumors.
  Journal
Biochemistry (Mosc) 70:576-83 (2005)
Reference
  Authors
Altucci L, Gronemeyer H.
  Title
The promise of retinoids to fight against cancer.
  Journal
Nat Rev Cancer 1:181-93 (2001)
DOI:10.1038/35106036
Reference
  Authors
Virmani AK, Rathi A, Zochbauer-Muller S, Sacchi N, Fukuyama Y, Bryant D, Maitra A, Heda S, Fong KM, Thunnissen F, Minna JD, Gazdar AF.
  Title
Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas.
  Journal
J Natl Cancer Inst 92:1303-7 (2000)
DOI:10.1093/jnci/92.16.1303
Reference
  Authors
Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA.
  Title
Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies.
  Journal
Lung Cancer 41 Suppl 1:S29-42 (2003)
DOI:10.1016/S0169-5002(03)00137-5
Reference
  Authors
Panani AD, Roussos C.
  Title
Cytogenetic and molecular aspects of lung cancer.
  Journal
Cancer Lett 239:1-9 (2006)
DOI:10.1016/j.canlet.2005.06.030
Reference
  Authors
Mitsuuchi Y, Testa JR.
  Title
Cytogenetics and molecular genetics of lung cancer.
  Journal
Am J Med Genet 115:183-8 (2002)
DOI:10.1002/ajmg.10692
Reference
  Authors
Breuer RH, Postmus PE, Smit EF.
  Title
Molecular pathology of non-small-cell lung cancer.
  Journal
Respiration 72:313-30 (2005)
DOI:10.1159/000085376
Reference
  Authors
Piyathilake CJ, Frost AR, Manne U, Weiss H, Bell WC, Heimburger DC, Grizzle WE.
  Title
Differential expression of growth factors in squamous cell carcinoma and precancerous lesions of the lung.
  Journal
Clin Cancer Res 8:734-44 (2002)
Reference
  Authors
Awaya H, Takeshima Y, Furonaka O, Kohno N, Inai K.
  Title
Gene amplification and protein expression of EGFR and HER2 by chromogenic in situ hybridisation and immunohistochemistry in atypical adenomatous hyperplasia and adenocarcinoma of the lung.
  Journal
J Clin Pathol 58:1076-80 (2005)
DOI:10.1136/jcp.2004.025585
Reference
  Authors
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H
  Title
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
  Journal
Nature 448:561-6 (2007)
DOI:10.1038/nature05945
Reference
  Authors
Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Hamada T, Haruta H, Watanabe H, Kurashina K, Hatanaka H, Ueno T, Takada S, Yamashita Y, Sugiyama Y, Ishikawa Y, Mano H
  Title
Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
  Journal
Cancer Res 68:4971-6 (2008)
DOI:10.1158/0008-5472.CAN-07-6158
Reference
  Authors
Janne PA, Gray N, Settleman J
  Title
Factors underlying sensitivity of cancers to small-molecule kinase inhibitors.
  Journal
Nat Rev Drug Discov 8:709-23 (2009)
DOI:10.1038/nrd2871
Reference
  Authors
Roskoski R Jr
  Title
Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition.
  Journal
Pharmacol Res 68:68-94 (2013)
DOI:10.1016/j.phrs.2012.11.007
Reference
  Authors
Reungwetwattana T, Weroha SJ, Molina JR
  Title
Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC).
  Journal
Clin Lung Cancer 13:252-66 (2012)
DOI:10.1016/j.cllc.2011.09.004
Reference
  Authors
Popat S, Gonzalez D, Min T, Swansbury J, Dainton M, Croud JG, Rice AJ, Nicholson AG
  Title
ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma.
  Journal
Lung Cancer 75:300-5 (2012)
DOI:10.1016/j.lungcan.2011.07.017
Reference
  Authors
Yoshida A, Tsuta K, Nakamura H, Kohno T, Takahashi F, Asamura H, Sekine I, Fukayama M, Shibata T, Furuta K, Tsuda H
  Title
Comprehensive histologic analysis of ALK-rearranged lung carcinomas.
  Journal
Am J Surg Pathol 35:1226-34 (2011)
DOI:10.1097/PAS.0b013e3182233e06
Reference
  Authors
Shaozhang Z, Xiaomei L, Aiping Z, Jianbo H, Xiangqun S, Qitao Y
  Title
Detection of EML4-ALK fusion genes in non-small cell lung cancer patients with clinical features associated with EGFR mutations.
  Journal
Genes Chromosomes Cancer 51:925-32 (2012)
DOI:10.1002/gcc.21976
Reference
  Authors
Toyooka S, Mitsudomi T, Soh J, Aokage K, Yamane M, Oto T, Kiura K, Miyoshi S
  Title
Molecular oncology of lung cancer.
  Journal
Gen Thorac Cardiovasc Surg 59:527-37 (2011)
DOI:10.1007/s11748-010-0743-3
Reference
  Authors
Koudelakova V, Kneblova M, Trojanec R, Drabek J, Hajduch M
  Title
Non-small cell lung cancer--genetic predictors.
  Journal
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 157:125-36 (2013)
DOI:10.5507/bp.2013.034
KO pathway
 

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