KEGG   PATHWAY: hsa05223Help
Entry
hsa05223                    Pathway                                

Name
Non-small cell lung cancer - Homo sapiens (human)
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, c-erbB-2 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. Overexpression of c-erbB-2 or 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
hsa05223

All organismsOrtholog table
Disease
H00014  
Non-small cell lung cancer
Drug
D01977  
Gefitinib (JAN/USAN/INN)
D02970  
Aprinocarsen sodium (USAN)
D04023  
Erlotinib hydrochloride (JAN/USAN)
D07907  
Erlotinib (INN)
D09731  
Crizotinib (JAN/USAN/INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
2272  
FHIT; fragile histidine triad [KO:K01522] [EC:3.6.1.29]
5915  
RARB; retinoic acid receptor beta [KO:K08528]
6256  
RXRA; retinoid X receptor alpha [KO:K08524]
6257  
RXRB; retinoid X receptor beta [KO:K08525]
6258  
RXRG; retinoid X receptor gamma [KO:K08526]
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; retinoblastoma 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]
3845  
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
11186  
RASSF1; Ras association domain family member 1 [KO:K09850]
83593  
RASSF5; Ras association domain family member 5 [KO:K08015]
6789  
STK4; serine/threonine kinase 4 [KO:K04411]
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]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5170  
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
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]
572  
BAD; BCL2 associated agonist of cell death [KO:K02158]
842  
CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
2309  
FOXO3; forkhead box O3 [KO:K09408]
1950  
EGF; epidermal growth factor [KO:K04357]
7039  
TGFA; transforming growth factor alpha [KO:K08774]
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]
2885  
GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  
SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  
SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  
HRAS; Harvey rat sarcoma viral oncogene homolog [KO:K02833]
4893  
NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
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]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [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]
5335  
PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5336  
PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
5578  
PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  
PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  
PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
7157  
TP53; tumor protein p53 [KO:K04451]
27436  
EML4; echinoderm microtubule associated protein like 4 [KO:K15420]
238  
ALK; anaplastic lymphoma receptor tyrosine kinase [KO:K05119] [EC:2.7.10.1]
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)
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)
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)
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)
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)
Reference
  Authors
Panani AD, Roussos C.
  Title
Cytogenetic and molecular aspects of lung cancer.
  Journal
Cancer Lett 239:1-9 (2006)
Reference
  Authors
Mitsuuchi Y, Testa JR.
  Title
Cytogenetics and molecular genetics of lung cancer.
  Journal
Am J Med Genet 115:183-8 (2002)
Reference
  Authors
Breuer RH, Postmus PE, Smit EF.
  Title
Molecular pathology of non-small-cell lung cancer.
  Journal
Respiration 72:313-30 (2005)
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)
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)
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)
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)
Reference
  Authors
Roskoski R Jr
  Title
Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition.
  Journal
Pharmacol Res 68:68-94 (2013)
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)
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)
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)
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)
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