KEGG   PATHWAY: ko05223Help
Entry
ko05223                     Pathway                                

Name
Non-small cell lung cancer
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
ko05223

All organismsOrtholog table
Disease
H00014  
Non-small cell lung cancer
Orthology
K01522  
bis(5'-adenosyl)-triphosphatase [EC:3.6.1.29]
K08528  
retinoic acid receptor beta
K08524  
retinoid X receptor alpha
K08525  
retinoid X receptor beta
K08526  
retinoid X receptor gamma
K06621  
cyclin-dependent kinase inhibitor 2A
K02089  
cyclin-dependent kinase 4 [EC:2.7.11.22]
K02091  
cyclin-dependent kinase 6 [EC:2.7.11.22]
K04503  
cyclin D1
K06618  
retinoblastoma-associated protein
K17454  
transcription factor E2F1
K09389  
transcription factor E2F2
K06620  
transcription factor E2F3
K07827  
GTPase KRas
K09850  
Ras association domain-containing protein 1
K08015  
Ras association domain-containing protein 5
K04411  
serine/threonine kinase 4
K00922  
phosphatidylinositol-4,5-bisphosphate 3-kinase [EC:2.7.1.153]
K02649  
phosphoinositide-3-kinase, regulatory subunit
K06276  
3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]
K04456  
RAC serine/threonine-protein kinase [EC:2.7.11.1]
K02158  
BCL2-antagonist of cell death
K04399  
caspase 9 [EC:3.4.22.62]
K09408  
forkhead box protein O3
K04357  
epidermal growth factor
K08774  
transforming growth factor, alpha
K04361  
epidermal growth factor receptor [EC:2.7.10.1]
K05083  
receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1]
K04364  
growth factor receptor-binding protein 2
K03099  
son of sevenless
K02833  
GTPase HRas
K07828  
GTPase NRas
K08845  
A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  
B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  
RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  
mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  
mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  
mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K01116  
phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K05859  
phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]
K02677  
classical protein kinase C [EC:2.7.11.13]
K04451  
tumor protein p53
K15420  
echinoderm microtubule-associated protein-like 4
K05119  
anaplastic lymphoma kinase [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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