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.f51ea7e17ff3d76parentid=P06400; parentsymbol=RB1; site=AVIPINGsPRtPRRG; position=ser249; sitegrpid=447975; ptm=p; direction=dparentid=P31749; parentsymbol=AKT1; site=kDGAtMKtFCGtPEy; position=thr308; sitegrpid=447856; ptm=ub; direction=uparentid=Q92934; parentsymbol=BAD; site=KGLPRPKsAGtAtQM; position=ser134; sitegrpid=447864; ptm=p; direction=dparentid=Q92934; parentsymbol=BAD; site=PFrGrsRsAPPNLWA; position=ser99; sitegrpid=447862; ptm=p; direction=dparentid=P31749; parentsymbol=AKT1; site=RPHFPQFsysAsGtA; position=ser473; sitegrpid=447855; ptm=ub; direction=uparentid=Q02750; parentsymbol=MAP2K1; site=LIDsMANsFVGtRSY; position=ser222; sitegrpid=448513; ptm=p; direction=uparentid=Q02750; parentsymbol=MAP2K1; site=VsGQLIDsMANsFVG; position=ser218; sitegrpid=448514; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=LIDsMANsFVGtRSY; position=ser226; sitegrpid=448074; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=VsGQLIDsMANsFVG; position=ser222; sitegrpid=448073; ptm=p; direction=uparentid=P28482; parentsymbol=MAPK1; site=HtGFLtEyVAtRWyr; position=tyr187; sitegrpid=447594; ptm=p; direction=uparentid=P28482; parentsymbol=MAPK1; site=HDHtGFLtEyVAtRW; position=thr185; sitegrpid=447593; ptm=p; direction=uparentid=P27361; parentsymbol=MAPK3; site=HDHtGFLtEyVAtRW; position=thr202; sitegrpid=447542; ptm=p; direction=uparentid=P27361; parentsymbol=MAPK3; site=HtGFLtEyVAtRWyr; position=tyr204; sitegrpid=447543; ptm=p; direction=uparentid=P19174; parentsymbol=PLCG1; site=EGsFEsRyQQPFEDF; position=tyr1253; sitegrpid=448576; ptm=p; direction=uparentid=P19174; parentsymbol=PLCG1; site=EGRNPGFyVEANPMP; position=tyr783; sitegrpid=447667; ptm=p; direction=uparentid=P19174; parentsymbol=PLCG1; site=IGtAEPdyGALyEGR; position=tyr771; sitegrpid=448575; ptm=p; direction=uparentid=P31751; parentsymbol=AKT2; site=sDGAtMKtFCGtPEy; position=thr309; sitegrpid=448537; ptm=p; direction=uparentid=P55211; parentsymbol=CASP9; site=kLRRRFssLHFMVEV; position=ser196; sitegrpid=448454; ptm=p; direction=dparent=O43524; position=ser253; ptm=p; direction=dparent=O43524; position=thr32; ptm=p; direction=dparentid=P42229; parentsymbol=STAT5A; site=LAkAVDGyVkPQIkQ; position=tyr694; sitegrpid=447767; ptm=p; direction=ub72d6717328863PubMedInduction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells.Biochem Biophys Res Commun2007Deng WGNishizaki MFang BRoth JAJi Llung cancer pathwayPW:0000703Pathway Ontology25514926PubMedPhosphoSitePlus, 2014: mutations, PTMs and recalibrations.Nucleic Acids Res2015Hornbeck PVZhang BMurray BKornhauser JMLatham VSkrzypek E17328863PubMedInduction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells.Biochem Biophys Res Commun2007Deng WGNishizaki MFang BRoth JAJi L28572459PubMedAACR Project GENIE: Powering Precision Medicine through an International Consortium.Cancer Discov201723322901PubMedMolecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment.Clin Cancer Res2013Connolly RMNguyen NKSukumar Sdisease pathwayPW:0000013Pathway Ontology20418096PubMedThe biology and treatment of EML4-ALK non-small cell lung cancer.Eur J Cancer2010Sasaki TRodig SJChirieac LRJänne PAmap05223KEGG PathwayKEGG Non-small cell lung cancerhttps://www.kegg.jp/dbget-bin/www_bget?pathway+map05223lung cancerDOID:1324Diseasecancer pathwayPW:0000605Pathway Ontologybronchial epithelial cellCL:0002328Cell Type