EGFR tyrosine kinase inhibitor resistance (Homo sapiens)

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Bypass pathwayKRASP12CCND1PMYCP49NucleusProtein synthesisVEGF/VEGFR abnormalityLow expressionDifferentiationGrowthProliferationSurvivalMotilityAngiogenesisAbnormal dimerizationof STAT3Impairment of apoptotic pathwayRPS6AXL8+PRKCADiacylglycerolSHC1IGF1R10EIF4EPDGFRAErlotinibApoptosisSRCHGF+BAXEpitheial-Mesenchymal TransitionIL6RPLCG1GefitinibSTAT3PJAK1BCL2L11PBCL2L13PTENFGFR2ERBB3PNRG1EGFRTGFAERBB2EGFEGFREGFR55EGFR5NRG21ERBB2ERBB3ERBB3IGF1VEGFAPDGFAPDGFBPDGFCPDGFDFGF2GAS6IL611+MET7METEGFR7KDR2PDGFRBFGFR3JAK2STAT3PPSTAT3PGAB1AKT1PPAKT2PAKT3PPIP3PDPK1PIP2GSK3BPBADPEIF4EBP1PPPMTORPFOXO3PPRPS6KB1PPRPS6KB2BIMEIF4E2PLCG2PRKCBPRKCGGRB2ARAFMAP2K1PPMAPK1PPBRAF6SOS2MAPK3PPSOS1HRASPNF1-13MAP2K2PPRAF1PPSHC2SHC3SHC4BCL2Tyrosine Kinase InhibitorsIneffective due to EGFR mutationSTAT3PPPIK3CALegend+Activating mutationInactivating mutation or loss of heterozygosityOverexpression-PIK3R3PIK3R1PPPIK3CDPIK3CBPPPPDGFR abnormalityFGFR activationIGF1R abnormalityNRASPMRASPRRASPRRAS2PPIK3R2


Description

Tyrosine kinase inhibitors (TKIs) are drugs that inhibit the phosphorylation, and subsequent activation, of tyrosine kinases. TKIs are typically used as cancer therapeutics, but development of resistance to TKIs in cancers is common. This pathway describes several mechanisms of TKI resistance in the context of EGFR signaling. Epidermal Growth Factor Receptor, EGFR, is a transmembrane tyrosine kinase that binds to the EGF-family of ligands. It activates several downstream signaling cascades, including MAPK, and leads to DNA synthesis and cell proliferation. Mutations and over-expression in EGFR is implicated in many cancers. The section of the pathway outlined in pink corresponds to mechanisms of TKI resistance.

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Bibliography

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  1. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA; ''MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.''; Science, 2007 PubMed Europe PMC Scholia
  2. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL, Pan Y, Wang L, de Stanchina E, Shien K, Aoe K, Toyooka S, Kiura K, Fernandez-Cuesta L, Fidias P, Yang JC, Miller VA, Riely GJ, Kris MG, Engelman JA, Vnencak-Jones CL, Dias-Santagata D, Ladanyi M, Pao W; ''Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.''; Proc Natl Acad Sci U S A, 2012 PubMed Europe PMC Scholia
  3. Akhavan D, Pourzia AL, Nourian AA, Williams KJ, Nathanson D, Babic I, Villa GR, Tanaka K, Nael A, Yang H, Dang J, Vinters HV, Yong WH, Flagg M, Tamanoi F, Sasayama T, James CD, Kornblum HI, Cloughesy TF, Cavenee WK, Bensinger SJ, Mischel PS; ''De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients.''; Cancer Discov, 2013 PubMed Europe PMC Scholia
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  8. Valtorta E, Misale S, Sartore-Bianchi A, Nagtegaal ID, Paraf F, Lauricella C, Dimartino V, Hobor S, Jacobs B, Ercolani C, Lamba S, Scala E, Veronese S, Laurent-Puig P, Siena S, Tejpar S, Mottolese M, Punt CJ, Gambacorta M, Bardelli A, Di Nicolantonio F; ''KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy.''; Int J Cancer, 2013 PubMed Europe PMC Scholia
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History

View all...
CompareRevisionActionTimeUserComment
127253view17:43, 28 August 2023Khanspersadded literature reference and updated description
127018view09:30, 19 July 2023Ash iyerMade datanode clickable.
127008view21:02, 18 July 2023Khanspersfixed typo, updated node sizing for readability
127007view20:55, 18 July 2023Khanspersadded phospho sites for JAK1/JAK2
127006view20:27, 17 July 2023KhanspersModified description
123492view04:50, 29 July 2022EgonwMade a pathway clickable
116801view10:04, 14 May 2021EweitzModified title
113761view15:19, 19 November 2020DeSlUpdated old HMDB IDs
112159view18:23, 29 September 2020Khanspersfixed ptm state comments
112037view05:43, 16 September 2020Khanspersupdated phospho sites
110852view19:55, 12 June 2020Khanspersdecreased board height
110851view19:54, 12 June 2020Khanspersdecreased board height
110734view22:19, 29 May 2020Khanspersfinal layout
110733view21:54, 29 May 2020Khanspersupdated layout
110732view21:02, 29 May 2020Khanspersupdating layout
110568view21:18, 18 May 2020Khanspersadded mutation info for BIM (BCL2L11)
110567view21:11, 18 May 2020Khanspersmutation info for KRAS, NF1, BRAF. Phospho site for RAF1.
110566view20:44, 18 May 2020Khanspersdetails of ERBB3 phosphorylation by c-met
110565view19:00, 18 May 2020KhanspersModified description
110564view17:38, 18 May 2020KhanspersOntology Term : 'altered tyrosine-specific protein kinase mediated signaling pathway' added !
110544view10:05, 18 May 2020Fehrhartfound the only unconnected line and fixed it
110509view00:18, 16 May 2020Khanspersadded lit refs and updated signaling
110508view21:14, 15 May 2020Khanspersupdated signaling
110507view20:48, 15 May 2020Khanspersadded lit refs for IL-6 and AXL
110313view22:03, 3 May 2020Marvin M2Connected unconnected lines
110305view06:45, 3 May 2020EgonwReplaced secondary ChEBI identifiers with a primary identifiers.
109041view19:36, 14 February 2020KhanspersOntology Term : 'altered growth factor signaling pathway' added !
109040view19:34, 14 February 2020KhanspersOntology Term : 'tyrosine-specific protein kinase mediated signaling pathway' added !
109039view19:34, 14 February 2020KhanspersModified title
109038view19:33, 14 February 2020KhanspersNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AKT1GeneProduct207 (Entrez Gene)
AKT2GeneProduct208 (Entrez Gene)
AKT3GeneProduct10000 (Entrez Gene)
ARAFGeneProductENSG00000078061 (Ensembl)
AXLGeneProductENSG00000167601 (Ensembl)
ApoptosisPathwayWP254 (WikiPathways)
BADGeneProduct572 (Entrez Gene)
BAXGeneProductENSG00000087088 (Ensembl)
BCL2GeneProductENSG00000171791 (Ensembl)
BCL2L11GeneProductENSG00000153094 (Ensembl)
BCL2L1GeneProductENSG00000171552 (Ensembl)
BIMGeneProductENSG00000153094 (Ensembl)
BRAFGeneProduct673 (Entrez Gene)
CCND1GeneProduct595 (Entrez Gene)
DiacylglycerolMetaboliteCHEBI:18035 (ChEBI)
EGFGeneProduct1950 (Entrez Gene)
EGFRGeneProduct1956 (Entrez Gene)
EGFRGeneProductENSG00000146648 (Ensembl)
EIF4E2GeneProductENSG00000135930 (Ensembl)
EIF4EBP1GeneProduct1978 (Entrez Gene)
EIF4EGeneProductENSG00000151247 (Ensembl)
ERBB2GeneProduct2064 (Entrez Gene)
ERBB3GeneProduct2065 (Entrez Gene)
Epitheial-Mesenchymal TransitionPathway
ErlotinibMetaboliteHMDB14671 (HMDB)
FGF2GeneProductENSG00000138685 (Ensembl)
FGFR2GeneProductENSG00000066468 (Ensembl)
FGFR3GeneProductENSG00000068078 (Ensembl)
FOXO3GeneProductENSG00000118689 (Ensembl)
GAB1GeneProduct2549 (Entrez Gene)
GAS6GeneProductENSG00000183087 (Ensembl)
GRB2GeneProduct2885 (Entrez Gene)
GSK3BGeneProductENSG00000082701 (Ensembl)
GefitinibMetaboliteCHEBI:49668 (ChEBI)
HGFGeneProductENSG00000019991 (Ensembl)
HRASGeneProductENSG00000174775 (Ensembl)
IGF1GeneProductENSG00000017427 (Ensembl)
IGF1RGeneProductENSG00000140443 (Ensembl)
IL6GeneProductENSG00000136244 (Ensembl)
IL6RGeneProductENSG00000160712 (Ensembl)
JAK1GeneProductENSG00000162434 (Ensembl)
JAK2GeneProductENSG00000096968 (Ensembl)
KDRGeneProductENSG00000128052 (Ensembl)
KRASGeneProduct3845 (Entrez Gene)
MAP2K1GeneProduct5604 (Entrez Gene)
MAP2K2GeneProduct5605 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
METGeneProductENSG00000105976 (Ensembl)
MRASGeneProduct22808 (Entrez Gene)
MTORGeneProduct2475 (Entrez Gene)
MYCGeneProduct4609 (Entrez Gene)
NF1GeneProductENSG00000196712 (Ensembl)
NRASGeneProduct4893 (Entrez Gene)
NRG1GeneProduct3084 (Entrez Gene)
NRG2GeneProduct9542 (Entrez Gene)
PDGFAGeneProductENSG00000197461 (Ensembl)
PDGFBGeneProductENSG00000100311 (Ensembl)
PDGFCGeneProductENSG00000145431 (Ensembl)
PDGFDGeneProductENSG00000170962 (Ensembl)
PDGFRAGeneProductENSG00000134853 (Ensembl)
PDGFRBGeneProductENSG00000113721 (Ensembl)
PDPK1GeneProductENSG00000140992 (Ensembl)
PIK3CAGeneProduct5290 (Entrez Gene)
PIK3CBGeneProduct5291 (Entrez Gene)
PIK3CDGeneProduct5293 (Entrez Gene)
PIK3R1GeneProduct5295 (Entrez Gene)
PIK3R2GeneProduct5296 (Entrez Gene)
PIK3R3GeneProduct8503 (Entrez Gene)
PIP2MetaboliteCHEBI:18348 (ChEBI)
PIP3MetaboliteHMDB0004249 (HMDB)
PLCG1GeneProductENSG00000124181 (Ensembl)
PLCG2GeneProductENSG00000197943 (Ensembl)
PRKCAGeneProductENSG00000154229 (Ensembl)
PRKCBGeneProductENSG00000166501 (Ensembl)
PRKCGGeneProductENSG00000126583 (Ensembl)
PTENGeneProductENSG00000171862 (Ensembl)
RAF1GeneProduct5894 (Entrez Gene)
RPS6GeneProductENSG00000137154 (Ensembl)
RPS6KB1GeneProduct6198 (Entrez Gene)
RPS6KB2GeneProduct6199 (Entrez Gene)
RRAS2GeneProductENSG00000133818 (Ensembl)
RRASGeneProductENSG00000126458 (Ensembl)
SHC1GeneProductENSG00000160691 (Ensembl)
SHC2GeneProductENSG00000129946 (Ensembl)
SHC3GeneProductENSG00000148082 (Ensembl)
SHC4GeneProductENSG00000185634 (Ensembl)
SOS1GeneProductENSG00000115904 (Ensembl)
SOS2GeneProduct6655 (Entrez Gene)
SRCGeneProductENSG00000197122 (Ensembl)
STAT3GeneProductENSG00000168610 (Ensembl)
TGFAGeneProduct7039 (Entrez Gene)
VEGFAGeneProductENSG00000112715 (Ensembl)

Annotated Interactions

No annotated interactions

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