KEGG   PATHWAY: pcw05223
Entry
pcw05223                    Pathway                                

Name
Non-small cell lung cancer - Phascolarctos cinereus (koala)
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
pcw05223  Non-small cell lung cancer
pcw05223

Organism
Phascolarctos cinereus (koala) [GN:pcw]
Gene
110201683  FHIT; bis(5'-adenosyl)-triphosphatase isoform X1 [KO:K01522] [EC:3.6.1.29]
110197316  RARB; retinoic acid receptor beta isoform X1 [KO:K08528]
110205364  RXRA; retinoic acid receptor RXR-alpha isoform X1 [KO:K08524]
110199336  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
110209882  RXRG; retinoic acid receptor RXR-gamma isoform X1 [KO:K08526]
110201193  cyclin-dependent kinase inhibitor 2A-like isoform X1 [KO:K06621]
110210989  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
110209152  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
110197171  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
110213446  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
110216806  E2F1; transcription factor E2F1 [KO:K17454]
110206051  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
110208713  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
110193352  KRAS; GTPase KRas isoform X1 [KO:K07827]
110217123  RASSF1; ras association domain-containing protein 1 isoform X1 [KO:K09850]
110219544  RASSF5; ras association domain-containing protein 5 [KO:K08015]
110206589  STK4; serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
110204454  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
110208219  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110199476  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
110223395  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
110216530  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110209293  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
110221981  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
110205475  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110202713  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110203042  AKT1; LOW QUALITY PROTEIN: RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110195467  BAD; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
110198824  CASP9; caspase-9 [KO:K04399] [EC:3.4.22.62]
110222927  FOXO3; forkhead box protein O3 [KO:K09408]
110218605  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
110207627  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
110204990  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
110215729  ERBB2; LOW QUALITY PROTEIN: receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
110206952  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
110202946  MET; hepatocyte growth factor receptor [KO:K05099] [EC:2.7.10.1]
110219266  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
110211774  SOS2; son of sevenless homolog 2 [KO:K03099]
110201388  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
110202954  HRAS; GTPase HRas isoform X1 [KO:K02833]
110219182  NRAS; GTPase NRas [KO:K07828]
110203410  GTPase NRas-like [KO:K07828]
110203411  GTPase HRas-like [KO:K07828]
110202309  GTPase HRas-like [KO:K07828]
110201017  ARAF; LOW QUALITY PROTEIN: serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
110216339  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
110204892  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
110205943  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
110197417  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
110221918  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
110215167  MAPK1; LOW QUALITY PROTEIN: mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
110216705  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
110212621  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
110218307  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
110214622  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
110220182  PRKCG; LOW QUALITY PROTEIN: protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
110194271  TP53; cellular tumor antigen p53 [KO:K04451]
110217257  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X1 [KO:K06625]
110212964  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
110223449  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
110195907  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
110219776  BAX; apoptosis regulator BAX [KO:K02159]
110217311  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
110223919  DDB2; LOW QUALITY PROTEIN: DNA damage-binding protein 2 [KO:K10140]
110216585  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
110210979  KIF5A; LOW QUALITY PROTEIN: kinesin heavy chain [KO:K10396]
110211255  KIF5B; kinesin-1 heavy chain isoform X1 [KO:K10396]
110207171  KIF5C; kinesin heavy chain [KO:K10396]
110221483  RET; proto-oncogene tyrosine-protein kinase receptor Ret isoform X1 [KO:K05126] [EC:2.7.10.1]
110218476  EML4; echinoderm microtubule-associated protein-like 4 isoform X1 [KO:K15420]
110206438  ALK; LOW QUALITY PROTEIN: ALK tyrosine kinase receptor [KO:K05119] [EC:2.7.10.1]
110223345  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
110198372  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
110198414  LOW QUALITY PROTEIN: signal transducer and activator of transcription 5A-like [KO:K11223]
110198412  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
pcw04010  MAPK signaling pathway
pcw04012  ErbB signaling pathway
pcw04014  Ras signaling pathway
pcw04020  Calcium signaling pathway
pcw04110  Cell cycle
pcw04115  p53 signaling pathway
pcw04151  PI3K-Akt signaling pathway
KO pathway
ko05223   
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