KEGG   PATHWAY: pale05223
Entry
pale05223                   Pathway                                

Name
Non-small cell lung cancer - Pteropus alecto (black flying fox)
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
pale05223  Non-small cell lung cancer
pale05223

Organism
Pteropus alecto (black flying fox) [GN:pale]
Gene
102883490  FHIT; bis(5'-adenosyl)-triphosphatase isoform X2 [KO:K01522] [EC:3.6.1.29]
102886545  RARB; retinoic acid receptor beta [KO:K08528]
102881572  RXRA; retinoic acid receptor RXR-alpha [KO:K08524]
102888877  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
102897820  RXRG; retinoic acid receptor RXR-gamma [KO:K08526]
102896422  LOW QUALITY PROTEIN: cyclin-dependent kinase inhibitor 2A [KO:K06621]
102894222  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
102896272  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
102885330  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
102893019  RB1; retinoblastoma-associated protein [KO:K06618]
102895276  E2F1; transcription factor E2F1 [KO:K17454]
102884459  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
102887239  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
102895590  KRAS; GTPase KRas isoform X1 [KO:K07827]
102879898  RASSF1; ras association domain-containing protein 1 isoform X1 [KO:K09850]
102888616  RASSF5; ras association domain-containing protein 5 isoform X2 [KO:K08015]
102881410  STK4; serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
102889227  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102880320  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102889576  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102879163  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102891637  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X3 [KO:K02649]
102879453  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102896950  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102885144  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102879337  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102898305  AKT2; LOW QUALITY PROTEIN: RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102877892  BAD; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
102878565  CASP9; caspase-9 [KO:K04399] [EC:3.4.22.62]
102890472  FOXO3; forkhead box protein O3 [KO:K09408]
102891552  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
102887662  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
102893495  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
102885300  ERBB2; LOW QUALITY PROTEIN: receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
102884470  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
102885990  MET; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:2.7.10.1]
102878822  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
102882462  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102889597  SOS2; son of sevenless homolog 2 [KO:K03099]
102896270  HRAS; GTPase HRas isoform X3 [KO:K02833]
102885950  NRAS; GTPase NRas isoform X2 [KO:K07828]
102877877  ARAF; serine/threonine-protein kinase A-Raf isoform X2 [KO:K08845] [EC:2.7.11.1]
102878393  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
102893439  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102897122  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
102879034  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102895390  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102885749  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102896228  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
102883128  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
102887078  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
102880663  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
102888961  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
102889604  TP53; cellular tumor antigen p53 [KO:K04451]
102894049  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
102886440  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
102878191  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
102885790  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
102885135  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
102883540  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
102879479  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
102890888  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
102891447  KIF5A; kinesin heavy chain isoform X4 [KO:K10396]
102893034  KIF5C; kinesin heavy chain [KO:K10396]
102894324  KIF5B; kinesin-1 heavy chain [KO:K10396]
102878133  RET; proto-oncogene tyrosine-protein kinase receptor Ret isoform X4 [KO:K05126] [EC:2.7.10.1]
102879824  EML4; echinoderm microtubule-associated protein-like 4 isoform X1 [KO:K15420]
102884662  ALK; ALK tyrosine kinase receptor [KO:K05119] [EC:2.7.10.1]
102898620  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
102884374  STAT3; LOW QUALITY PROTEIN: signal transducer and activator of transcription 3 [KO:K04692]
102884638  signal transducer and activator of transcription 5A [KO:K11223]
102884882  signal transducer and activator of transcription 5B isoform X1 [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
pale04010  MAPK signaling pathway
pale04012  ErbB signaling pathway
pale04014  Ras signaling pathway
pale04020  Calcium signaling pathway
pale04110  Cell cycle
pale04115  p53 signaling pathway
pale04151  PI3K-Akt signaling pathway
KO pathway
ko05223   
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