KEGG   PATHWAY: sbq05223
Entry
sbq05223                    Pathway                                

Name
Non-small cell lung cancer - Saimiri boliviensis boliviensis (Bolivian squirrel monkey)
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
sbq05223  Non-small cell lung cancer
sbq05223

Organism
Saimiri boliviensis boliviensis (Bolivian squirrel monkey) [GN:sbq]
Gene
101053087  FHIT; bis(5'-adenosyl)-triphosphatase [KO:K01522] [EC:3.6.1.29]
101053144  RARB; retinoic acid receptor beta isoform X2 [KO:K08528]
101044148  RXRA; retinoic acid receptor RXR-alpha [KO:K08524]
101040304  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
101040247  RXRG; retinoic acid receptor RXR-gamma isoform X1 [KO:K08526]
101038444  cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3 [KO:K06621]
101040767  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
101040507  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
101047858  CCND1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
101038309  RB1; retinoblastoma-associated protein [KO:K06618]
101029045  E2F1; transcription factor E2F1 [KO:K17454]
101042612  E2F2; transcription factor E2F2 [KO:K09389]
101034207  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
101047035  KRAS; GTPase KRas isoform X1 [KO:K07827]
101037299  RASSF1; ras association domain-containing protein 1 isoform X1 [KO:K09850]
101054503  RASSF5; ras association domain-containing protein 5 isoform X1 [KO:K08015]
101046861  STK4; serine/threonine-protein kinase 4 [KO:K04411]
101029768  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101052779  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101027982  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101032496  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101033359  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101050592  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101032521  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101034861  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101045714  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101040766  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101049631  BAD; bcl2-associated agonist of cell death [KO:K02158]
101051525  CASP9; caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
101039948  FOXO3; forkhead box protein O3 [KO:K09408]
101052478  EGF; pro-epidermal growth factor [KO:K04357]
101045311  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
101047461  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
101043415  ERBB2; receptor tyrosine-protein kinase erbB-2 isoform X2 [KO:K05083] [EC:2.7.10.1]
101045517  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
101038696  MET; hepatocyte growth factor receptor isoform X2 [KO:K05099] [EC:2.7.10.1]
101038666  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
101036943  SOS1; son of sevenless homolog 1 [KO:K03099]
101046427  SOS2; son of sevenless homolog 2 [KO:K03099]
101047663  HRAS; GTPase HRas isoform X2 [KO:K02833]
101036877  NRAS; GTPase NRas [KO:K07828]
101043605  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101052142  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
101054052  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
101040361  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101036151  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101038546  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101043202  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101046976  PLCG1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
101030999  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
101046010  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
101039384  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101032613  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
101043647  TP53; cellular tumor antigen p53 [KO:K04451]
101041919  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X2 [KO:K06625]
101030208  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
101039106  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
101047513  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
101050177  BAX; apoptosis regulator BAX [KO:K02159]
101041291  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
101027903  DDB2; DNA damage-binding protein 2 isoform X2 [KO:K10140]
101034259  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
101042531  KIF5B; kinesin-1 heavy chain [KO:K10396]
101054225  KIF5C; kinesin heavy chain isoform 5C [KO:K10396]
101034824  KIF5A; kinesin heavy chain isoform 5A [KO:K10396]
101053966  RET; proto-oncogene tyrosine-protein kinase receptor Ret [KO:K05126] [EC:2.7.10.1]
101039462  EML4; echinoderm microtubule-associated protein-like 4 isoform X2 [KO:K15420]
101044905  ALK; ALK tyrosine kinase receptor [KO:K05119] [EC:2.7.10.1]
101034707  JAK3; LOW QUALITY PROTEIN: tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
101049662  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
101049987  signal transducer and activator of transcription 5A [KO:K11223]
101043203  STAT5B; 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
sbq04010  MAPK signaling pathway
sbq04012  ErbB signaling pathway
sbq04014  Ras signaling pathway
sbq04020  Calcium signaling pathway
sbq04110  Cell cycle
sbq04115  p53 signaling pathway
sbq04151  PI3K-Akt signaling pathway
KO pathway
ko05223   
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