EGFR tyrosine kinase inhibitor resistance (Homo sapiens)

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Bypass pathwayKRASP4CCND1PMYCP86NucleusLow expressionVEGF/VEGFR abnormalityProtein synthesisDifferentiationGrowthProliferationSurvivalMotilityAngiogenesisAbnormal dimerizationof STAT3Impairment of apoptotic pathwayRPS6AXL12+PRKCADiacylglycerolSHC1IGF1R9EIF4EPDGFRAErlotinibApoptosisSRCHGF+BAXEpitheial-Mesenchymal TransitionIL6RPLCG1GefitinibSTAT3PJAK1BCL2L11PBCL2L15PTENFGFR2ERBB3PNRG1EGFRTGFAERBB2EGFEGFR3EGFR3EGFR3NRG211ERBB2ERBB3ERBB3IGF1VEGFAPDGFAPDGFBPDGFCPDGFDFGF2GAS6IL610+MET7MET7EGFRKDR1PDGFRBFGFR3JAK2STAT3PPSTAT3PGAB1AKT1PPAKT2PAKT3PPIP3PDPK1PIP2GSK3BPBADPEIF4EBP1PPPPMTORPFOXO3PPRPS6KB1PPRPS6KB2BIMEIF4E2PLCG2PRKCBPRKCGGRB2ARAFMAP2K1PPMAPK1PPBRAF13SOS2MAPK3PPSOS1HRASPNF1-2MAP2K2PPRAF1PPSHC2SHC3SHC4BCL2Tyrosine Kinase InhibitorsIneffective due to EGFR mutationSTAT3PPPIK3CALegend+Activating mutationInactivating mutation or loss of heterozygosityOverexpression-PIK3R3PIK3R1PIK3CDPPIK3CBPPPDGFR abnormalityFGFR activationIGF1R abnormalityNRASPMRASPRRASPRRAS2PPIK3R2PP


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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  1. Kuan CT, Wikstrand CJ, Bigner DD; ''EGF mutant receptor vIII as a molecular target in cancer therapy.''; Endocr Relat Cancer, 2001 PubMed Europe PMC Scholia
  2. de Bruin EC, Cowell C, Warne PH, Jiang M, Saunders RE, Melnick MA, Gettinger S, Walther Z, Wurtz A, Heynen GJ, Heideman DA, Gómez-Román J, García-Castaño A, Gong Y, Ladanyi M, Varmus H, Bernards R, Smit EF, Politi K, Downward J; ''Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.''; Cancer Discov, 2014 PubMed Europe PMC Scholia
  3. '''';,
  4. 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
  5. Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, Ariyaratne PN, Takahashi N, Sawada K, Fei Y, Soh S, Lee WH, Huang JW, Allen JC Jr, Woo XY, Nagarajan N, Kumar V, Thalamuthu A, Poh WT, Ang AL, Mya HT, How GF, Yang LY, Koh LP, Chowbay B, Chang CT, Nadarajan VS, Chng WJ, Than H, Lim LC, Goh YT, Zhang S, Poh D, Tan P, Seet JE, Ang MK, Chau NM, Ng QS, Tan DS, Soda M, Isobe K, Nöthen MM, Wong TY, Shahab A, Ruan X, Cacheux-Rataboul V, Sung WK, Tan EH, Yatabe Y, Mano H, Soo RA, Chin TM, Lim WT, Ruan Y, Ong ST; ''A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.''; Nat Med, 2012 PubMed Europe PMC Scholia
  6. 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
  7. 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
  8. Azuma K, Kawahara A, Sonoda K, Nakashima K, Tashiro K, Watari K, Izumi H, Kage M, Kuwano M, Ono M, Hoshino T; ''FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor.''; Oncotarget, 2014 PubMed Europe PMC Scholia
  9. Denduluri SK, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed MK, Ye J, Wei Q, Wang J, Zhao L, Luu HH; ''Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance.''; Genes Dis, 2015 PubMed Europe PMC Scholia
  10. Conze D, Weiss L, Regen PS, Bhushan A, Weaver D, Johnson P, Rincón M; ''Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells.''; Cancer Res, 2001 PubMed Europe PMC Scholia
  11. Huang TH, Wu F, Loeb GB, Hsu R, Heidersbach A, Brincat A, Horiuchi D, Lebbink RJ, Mo YY, Goga A, McManus MT; ''Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.''; J Biol Chem, 2009 PubMed Europe PMC Scholia
  12. Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B; ''AXL kinase as a novel target for cancer therapy.''; Oncotarget, 2014 PubMed Europe PMC Scholia
  13. 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


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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


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
ErlotinibMetaboliteHMDB0014671 (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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