KEGG   PATHWAY: mlf05223
Entry
mlf05223                    Pathway                                
Name
Non-small cell lung cancer - Myotis lucifugus (little brown bat)
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
mlf05223  Non-small cell lung cancer
mlf05223

Organism
Myotis lucifugus (little brown bat) [GN:mlf]
Gene
102428370  FHIT; bis(5'-adenosyl)-triphosphatase [KO:K01522] [EC:3.6.1.29]
102421956  bis(5'-adenosyl)-triphosphatase [KO:K01522] [EC:3.6.1.29]
102425322  RARB; retinoic acid receptor beta isoform X1 [KO:K08528]
102430829  RXRA; retinoic acid receptor RXR-alpha [KO:K08524]
102442015  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
102437396  RXRG; retinoic acid receptor RXR-gamma [KO:K08526]
102419422  cyclin-dependent kinase inhibitor 2A [KO:K06621]
102431798  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
102430068  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
102441858  CCND1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
102436007  RB1; LOW QUALITY PROTEIN: retinoblastoma-associated protein [KO:K06618]
102421766  E2F1; LOW QUALITY PROTEIN: transcription factor E2F1 [KO:K17454]
102418995  E2F2; transcription factor E2F2 [KO:K09389]
102422093  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
102431999  KRAS; GTPase KRas isoform X1 [KO:K07827]
102422877  RASSF1; ras association domain-containing protein 1 isoform X2 [KO:K09850]
102442160  RASSF5; ras association domain-containing protein 5 [KO:K08015]
102429707  STK4; serine/threonine-protein kinase 4 isoform X1 [KO:K04411]
102422649  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102441064  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102433534  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102427890  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102441522  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102429230  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102426106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102419324  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102431196  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102443221  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102439923  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102437980  BAD; bcl2-associated agonist of cell death [KO:K02158]
102428235  CASP9; caspase-9 isoform X2 [KO:K04399] [EC:3.4.22.62]
102440021  FOXO3; forkhead box protein O3 [KO:K09408]
102424256  EGF; pro-epidermal growth factor [KO:K04357]
102434624  TGFA; protransforming growth factor alpha isoform X2 [KO:K08774]
102435209  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
102427788  ERBB2; receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
102441297  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
102441042  MET; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:2.7.10.1]
102421027  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
102442926  SOS1; son of sevenless homolog 1 [KO:K03099]
102437531  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
102430744  NRAS; GTPase NRas [KO:K07828]
102420799  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
102435241  BRAF; LOW QUALITY PROTEIN: serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
102434453  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102417411  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
102423748  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102417755  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102422236  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102421330  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
102420000  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X2 [KO:K05859] [EC:3.1.4.11]
102438932  PRKCA; protein kinase C alpha type isoform X2 [KO:K02677] [EC:2.7.11.13]
102428240  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
102419083  protein kinase C gamma type-like [KO:K19663] [EC:2.7.11.13]
102431418  TP53; cellular tumor antigen p53 isoform X2 [KO:K04451]
102439094  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X2 [KO:K06625]
102428736  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
102427327  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X1 [KO:K04402]
102429644  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
102417074  BAX; apoptosis regulator BAX [KO:K02159]
102437326  BAK1; LOW QUALITY PROTEIN: bcl-2 homologous antagonist/killer [KO:K14021]
102422583  DDB2; DNA damage-binding protein 2 [KO:K10140]
102435990  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
102437811  KIF5A; kinesin heavy chain isoform X1 [KO:K10396]
102437778  KIF5C; kinesin heavy chain [KO:K10396]
102436848  KIF5B; LOW QUALITY PROTEIN: kinesin-1 heavy chain [KO:K10396]
102420377  RET; LOW QUALITY PROTEIN: proto-oncogene tyrosine-protein kinase receptor Ret [KO:K05126] [EC:2.7.10.1]
102416924  EML4; echinoderm microtubule-associated protein-like 4 isoform X2 [KO:K15420]
102423499  ALK; ALK tyrosine kinase receptor [KO:K05119] [EC:2.7.10.1]
102428976  JAK3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
102422489  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
102423996  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
102424720  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
mlf04010  MAPK signaling pathway
mlf04012  ErbB signaling pathway
mlf04014  Ras signaling pathway
mlf04020  Calcium signaling pathway
mlf04110  Cell cycle
mlf04115  p53 signaling pathway
mlf04151  PI3K-Akt signaling pathway
KO pathway
ko05223   
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