KEGG   PATHWAY: ocu05223
Entry
ocu05223                    Pathway                                

Name
Non-small cell lung cancer - Oryctolagus cuniculus (rabbit)
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; Cancer: specific types
Pathway map
ocu05223  Non-small cell lung cancer
ocu05223

Organism
Oryctolagus cuniculus (rabbit) [GN:ocu]
Gene
100356299  FHIT; fragile histidine triad [KO:K01522] [EC:3.6.1.29]
100358445  RARB; retinoic acid receptor beta [KO:K08528]
100354287  RXRB; retinoid X receptor beta [KO:K08525]
100340625  CDKN2A; cyclin-dependent kinase inhibitor 2A [KO:K06621]
100009039  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
100009040  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
100357431  RB1; RB transcriptional corepressor 1 [KO:K06618]
100356957  E2F1; E2F transcription factor 1 [KO:K17454]
100346379  E2F2; E2F transcription factor 2 [KO:K09389]
100353173  E2F3; E2F transcription factor 3 [KO:K06620]
100347487  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
100340832  RASSF1; Ras association domain family member 1 [KO:K09850]
100345444  RASSF5; Ras association domain family member 5 [KO:K08015]
100358822  STK4; serine/threonine kinase 4 [KO:K04411]
100348663  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
100345181  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
100337822  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
100357841  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
100345250  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100347954  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
100342852  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
100353706  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
100358587  BAD; BCL2 associated agonist of cell death [KO:K02158]
100101592  CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
100343573  FOXO3; forkhead box O3 [KO:K09408]
100008808  EGF; epidermal growth factor [KO:K04357]
100009482  TGFA; transforming growth factor alpha [KO:K08774]
100008806  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
100009554  ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
100316908  HGF; hepatocyte growth factor [KO:K05460]
100126565  MET; MET proto-oncogene, receptor tyrosine kinase [KO:K05099] [EC:2.7.10.1]
100342500  GRB2; growth factor receptor bound protein 2 [KO:K04364]
100356615  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
100346391  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
100344241  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
100340437  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
100351964  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
100347407  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
100009316  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100347345  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100348561  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100349958  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
100340139  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
100037720  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
100037719  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
100009102  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
100009292  TP53; tumor protein p53 [KO:K04451]
100348489  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
100353284  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
100353742  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
100355675  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
100342046  BAK1; BCL2 antagonist/killer 1 [KO:K14021]
100352386  DDB2; damage specific DNA binding protein 2 [KO:K10140]
100352218  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
100352693  KIF5B; kinesin family member 5B [KO:K10396]
100339597  KIF5A; kinesin family member 5A [KO:K10396]
100348141  KIF5C; kinesin family member 5C [KO:K10396]
100340710  RET; ret proto-oncogene [KO:K05126] [EC:2.7.10.1]
100352828  EML4; echinoderm microtubule associated protein like 4 [KO:K15420]
100347722  ALK; anaplastic lymphoma receptor tyrosine kinase [KO:K05119] [EC:2.7.10.1]
100348778  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
100348518  signal transducer and activator of transcription 5A [KO:K11223]
100348267  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)
DOI:10.1023/a:1022978932215
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)
DOI:10.1007/s10541-005-0151-y
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
Reference
  Authors
Takeuchi K
  Title
Discovery Stories of RET Fusions in Lung Cancer: A Mini-Review.
  Journal
Front Physiol 10:216 (2019)
DOI:10.3389/fphys.2019.00216
Reference
  Authors
Ferrara R, Auger N, Auclin E, Besse B
  Title
Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer.
  Journal
J Thorac Oncol 13:27-45 (2018)
DOI:10.1016/j.jtho.2017.10.021
Reference
  Authors
Santoro M, Moccia M, Federico G, Carlomagno F
  Title
RET Gene Fusions in Malignancies of the Thyroid and Other Tissues.
  Journal
Genes (Basel) 11:genes11040424 (2020)
DOI:10.3390/genes11040424
Related
pathway
ocu04010  MAPK signaling pathway
ocu04012  ErbB signaling pathway
ocu04014  Ras signaling pathway
ocu04020  Calcium signaling pathway
ocu04110  Cell cycle
ocu04115  p53 signaling pathway
ocu04151  PI3K-Akt signaling pathway
KO pathway
ko05223   
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