Non-small cell lung cancer (Homo sapiens)

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2, 4, 76LegendERProliferationDNA DamageActivating mutationAnti-apoptosisTGFATP53DAGRASSF1CDK4JAK3CDKN2ACalcium Signaling PathwayEGFRIP3AKT1PIP3RB1omacetaxine mepesuccinateCa2+RARBBADPIK3R1Retinoic acidCRABP1HRASPRKCAcobimetinibselumetinibEML4PDK1PIK3CAtrametinibpimasertibCDKN1AKRASBAK1EGFSTK4binimetinibERBB2PPPPPGRB2SOS1SOS2KRASNRASARAFBRAFRAF1MAP2K1MAP2K2PPPPMAPK1PMAPK3PPPPLCG1PPPLCG2PPRKCBPRKCGPIK3CBPIK3CDAKT2AKT3PCASP9PFOXO3PPPI3K-Akt Signaling PathwayALK5STAT3STAT5APSTAT5BCell survivalPIK3CAPIK3CBPIK3CDPIK3R2PIK3R3Ras Signaling PathwayCCND1RASSF5Reduced apoptosisRXRARXRBRXRGCDK6CCND1E2F1E2F2E2F3G1 to S progressionp53 Signaling PathwayCell CycleCell CycleBAXDDB2GADD45AGADD45BGADD45GPOLKInactivating mutation1CASP8FHITBID3Reduced apoptosisCell-cycle progressionCASP3CASP9CYCSRetinoic acidCRABP2Uncontrolled proliferationIncreased survivalGenomic instabilityTumor progression


Description

Non-small cell lung cancer (NSCLC) represents 85% of lung cancer and is defined as any type of epithelial lung cancer that is NOT small cell carcinoma, including squamous cell (SCC), adeno (AC) and large-cell carcinoma.

Mutations in NSCLC:

  • KRAS (mutated in ~29% of NSCLC patients) inactivates its GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus.
  • Mutations or overexpression of EGFR (~22% of NSCLC patients) leads to increased proliferation.
  • The abnormal fusion of EML4-ALK (~5% of NSCLC patients) leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis.
  • Inactivating mutation of p53 (~50% of NSCLC patients) leads to reduced apoptosis and proliferation.
  • The protein encoded by the p16INK4a, CDKN2A, inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. p16INK4a is mutated in ~12% of NSCLC patients, which leads to a loss of this inhibitory effect.
  • RARB is a nuclear retinoic acid receptor whose function is often lost in NSCLC, leading to a loss of cell growth control.
This pathway was developed based on https://www.kegg.jp/dbget-bin/www_bget?pathway+map05223. Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.

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Ontology Terms

 

Bibliography

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  1. Deng WG, Nishizaki M, Fang B, Roth JA, Ji L; ''Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells.''; Biochem Biophys Res Commun, 2007 PubMed Europe PMC Scholia
  2. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E; ''PhosphoSitePlus, 2014: mutations, PTMs and recalibrations.''; Nucleic Acids Res, 2015 PubMed Europe PMC Scholia
  3. Deng WG, Nishizaki M, Fang B, Roth JA, Ji L; ''Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells.''; Biochem Biophys Res Commun, 2007 PubMed Europe PMC Scholia
  4. ''AACR Project GENIE: Powering Precision Medicine through an International Consortium.''; Cancer Discov, 2017 PubMed Europe PMC Scholia
  5. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA; ''The biology and treatment of EML4-ALK non-small cell lung cancer.''; Eur J Cancer, 2010 PubMed Europe PMC Scholia
  6. Connolly RM, Nguyen NK, Sukumar S; ''Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment.''; Clin Cancer Res, 2013 PubMed Europe PMC Scholia
  7. ''KEGG Non-small cell lung cancer''; https://www.kegg.jp/dbget-bin/www_bget?pathway+map05223,

History

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CompareRevisionActionTimeUserComment
127755view18:51, 2 December 2023EgonwChEBI id for Ca2+ instead of the "Ca" atom
127573view17:25, 23 October 2023KhanspersModified description
127490view17:13, 11 October 2023Khanspersupdated phosphosites
127237view20:18, 25 August 2023Khanspersadded lit ref and updated description
123348view10:42, 17 July 2022EgonwMade five pathways clickable
119279view10:42, 23 June 2021Finterlyadded KEGG pathway info to publicationXref
108128view10:28, 29 November 2019FehrhartOntology Term : 'lung cancer' added !
108127view10:28, 29 November 2019FehrhartOntology Term : 'cancer pathway' added !
105677view22:54, 12 August 2019Khanspersadded drugs
105676view22:28, 12 August 2019Khanspersupdated outcomes
105481view05:38, 8 August 2019KhanspersModified description
105444view04:55, 8 August 2019KhanspersModified description
105192view23:10, 17 July 2019KhanspersModified description
105191view23:09, 17 July 2019Khanspersupdated lit refs
105190view22:42, 17 July 2019Khanspersupdated ERBB2
105189view22:33, 17 July 2019Khanspersadded lit ref
105155view23:21, 12 July 2019Khanspersadded details for retinoic acid signaling and added new interaction type
105154view22:21, 12 July 2019Khanspersupdate FHIT section
105004view04:55, 28 June 2019KhanspersModified description
96916view14:37, 19 April 2018EgonwReplaced secondary ChEBI identifiers with primary identifiers.
96911view04:38, 19 April 2018Khanspersupdated kras
96909view19:34, 18 April 2018Khanspersadded pathway node xrefs
96857view23:28, 14 April 2018AlexanderPicoOntology Term : 'disease pathway' added !
96856view00:06, 14 April 2018KhanspersOntology Term : 'bronchial epithelial cell' added !
96855view00:05, 14 April 2018KhanspersOntology Term : 'lung cancer pathway' added !
96854view00:05, 14 April 2018KhanspersModified description
96853view00:03, 14 April 2018KhanspersModified description
96852view23:58, 13 April 2018KhanspersNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl)
AKT2GeneProductENSG00000105221 (Ensembl)
AKT3GeneProductENSG00000117020 (Ensembl)
ALKGeneProductENSG00000171094 (Ensembl)
ARAFGeneProductENSG00000078061 (Ensembl)
BADGeneProductENSG00000002330 (Ensembl)
BAK1GeneProductENSG00000030110 (Ensembl)
BAXGeneProductENSG00000087088 (Ensembl)
BIDGeneProductENSG00000015475 (Ensembl)
BRAFGeneProductENSG00000157764 (Ensembl)
CASP3GeneProductENSG00000164305 (Ensembl)
CASP8GeneProductENSG00000064012 (Ensembl)
CASP9GeneProductENSG00000132906 (Ensembl)
CCND1GeneProductENSG00000110092 (Ensembl)
CDK4GeneProductENSG00000135446 (Ensembl)
CDK6GeneProductENSG00000105810 (Ensembl)
CDKN1AGeneProductENSG00000124762 (Ensembl)
CDKN2AGeneProductENSG00000147889 (Ensembl)
CRABP1GeneProductENSG00000166426 (Ensembl)
CRABP2GeneProductENSG00000143320 (Ensembl)
CYCSGeneProductENSG00000172115 (Ensembl)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calcium Signaling PathwayPathway
Cell CyclePathwayWP179 (WikiPathways)
DAGMetaboliteCHEBI:18035 (ChEBI)
DDB2GeneProductENSG00000134574 (Ensembl)
E2F1GeneProductENSG00000101412 (Ensembl)
E2F2GeneProductENSG00000007968 (Ensembl)
E2F3GeneProductENSG00000112242 (Ensembl)
EGFGeneProductENSG00000138798 (Ensembl)
EGFRGeneProductENSG00000146648 (Ensembl)
EML4GeneProductENSG00000143924 (Ensembl)
ERBB2GeneProductENSG00000141736 (Ensembl)
FHITGeneProductENSG00000189283 (Ensembl)
FOXO3GeneProductENSG00000118689 (Ensembl)
GADD45AGeneProductENSG00000116717 (Ensembl)
GADD45BGeneProductENSG00000099860 (Ensembl)
GADD45GGeneProductENSG00000130222 (Ensembl)
GRB2GeneProductGRB2 (HGNC)
HRASGeneProductENSG00000174775 (Ensembl)
IP3MetaboliteCHEBI:16595 (ChEBI)
JAK3GeneProductENSG00000105639 (Ensembl)
KRASGeneProductENSG00000133703 (Ensembl)
MAP2K1GeneProductENSG00000169032 (Ensembl)
MAP2K2GeneProductENSG00000126934 (Ensembl)
MAPK1GeneProductENSG00000100030 (Ensembl)
MAPK3GeneProductENSG00000102882 (Ensembl)
NRASGeneProductENSG00000213281 (Ensembl)
PDK1GeneProductENSG00000152256 (Ensembl)
PI3K-Akt Signaling PathwayPathwayWP4172 (WikiPathways)
PIK3CAGeneProductENSG00000121879 (Ensembl)
PIK3CBGeneProductENSG00000051382 (Ensembl)
PIK3CDGeneProductENSG00000171608 (Ensembl)
PIK3R1GeneProductENSG00000145675 (Ensembl)
PIK3R2GeneProductENSG00000105647 (Ensembl)
PIK3R3GeneProductENSG00000117461 (Ensembl)
PIP3MetaboliteCHEBI:16618 (ChEBI)
PLCG1GeneProductENSG00000124181 (Ensembl)
PLCG2GeneProductENSG00000197943 (Ensembl)
POLKGeneProductENSG00000122008 (Ensembl)
PRKCAGeneProductENSG00000154229 (Ensembl)
PRKCBGeneProductENSG00000166501 (Ensembl)
PRKCGGeneProductENSG00000126583 (Ensembl)
RAF1GeneProductENSG00000132155 (Ensembl)
RARBGeneProductENSG00000077092 (Ensembl)
RASSF1GeneProductENSG00000068028 (Ensembl)
RASSF5GeneProductENSG00000266094 (Ensembl)
RB1GeneProductENSG00000139687 (Ensembl)
RXRAGeneProductENSG00000186350 (Ensembl)
RXRBGeneProductENSG00000204231 (Ensembl)
RXRGGeneProductENSG00000143171 (Ensembl)
Ras Signaling PathwayPathwayWP4223 (WikiPathways)
Retinoic acidMetaboliteCHEBI:6067 (ChEBI)
SOS1GeneProductENSG00000115904 (Ensembl)
SOS2GeneProductENSG00000100485 (Ensembl)
STAT3GeneProductENSG00000168610 (Ensembl)
STAT5AGeneProductENSG00000126561 (Ensembl)
STAT5BGeneProductENSG00000173757 (Ensembl)
STK4GeneProductENSG00000101109 (Ensembl)
TGFAGeneProductENSG00000163235 (Ensembl)
TP53GeneProductENSG00000141510 (Ensembl)
binimetinibMetaboliteQ19903515 (Wikidata)
cobimetinibMetaboliteQ15708292 (Wikidata)
omacetaxine mepesuccinateMetaboliteCHEBI:71019 (ChEBI)
p53 Signaling PathwayPathwayWP707 (WikiPathways)
pimasertibMetaboliteQ27088393 (Wikidata)
selumetinibMetaboliteCHEBI:90227 (ChEBI)
trametinibMetaboliteQ7833138 (Wikidata)

Annotated Interactions

No annotated interactions

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