EGFR tyrosine kinase inhibitor resistance (WP4806)

Homo sapiens

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. This pathway was based on [ KEGG]. Protein phosphorylation sites were added based on information from PhosphoSitePlus (R),


Kristina Hanspers , Egon Willighagen , Marvin Martens , Friederike Ehrhart , Denise Slenter , Eric Weitz , and Ash Iyer


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Homo sapiens




Pathway Ontology

altered tyrosine-specific protein kinase mediated signaling pathway tyrosine-specific protein kinase mediated signaling pathway altered growth factor signaling pathway


Label Type Compact URI Comment
Diacylglycerol Metabolite chebi:18035
Erlotinib Metabolite hmdb:HMDB0014671
Gefitinib Metabolite chebi:49668
PIP3 Metabolite hmdb:HMDB0004249
PIP2 Metabolite chebi:18348
KRAS GeneProduct ncbigene:3845
CCND1 GeneProduct ncbigene:595
MYC GeneProduct ncbigene:4609
RPS6 GeneProduct ensembl:ENSG00000137154
AXL GeneProduct ensembl:ENSG00000167601
PRKCA GeneProduct ensembl:ENSG00000154229
SHC1 GeneProduct ensembl:ENSG00000160691
IGF1R GeneProduct ensembl:ENSG00000140443
EIF4E GeneProduct ensembl:ENSG00000151247
PDGFRA GeneProduct ensembl:ENSG00000134853
SRC GeneProduct ensembl:ENSG00000197122
HGF GeneProduct ensembl:ENSG00000019991
BAX GeneProduct ensembl:ENSG00000087088
IL6R GeneProduct ensembl:ENSG00000160712
PLCG1 GeneProduct ensembl:ENSG00000124181
STAT3 GeneProduct ensembl:ENSG00000168610
JAK1 GeneProduct ensembl:ENSG00000162434
BCL2L11 GeneProduct ensembl:ENSG00000153094
BCL2L1 GeneProduct ensembl:ENSG00000171552
PTEN GeneProduct ensembl:ENSG00000171862
FGFR2 GeneProduct ensembl:ENSG00000066468
ERBB3 GeneProduct ncbigene:2065
NRG1 GeneProduct ncbigene:3084
EGFR GeneProduct ncbigene:1956
TGFA GeneProduct ncbigene:7039
ERBB2 GeneProduct ncbigene:2064
EGF GeneProduct ncbigene:1950
EGFR GeneProduct ncbigene:1956
EGFR GeneProduct ensembl:ENSG00000146648
EGFR GeneProduct ncbigene:1956
NRG2 GeneProduct ncbigene:9542
ERBB2 GeneProduct ncbigene:2064
ERBB3 GeneProduct ncbigene:2065
ERBB3 GeneProduct ncbigene:2065
IGF1 GeneProduct ensembl:ENSG00000017427
VEGFA GeneProduct ensembl:ENSG00000112715
PDGFA GeneProduct ensembl:ENSG00000197461
PDGFB GeneProduct ensembl:ENSG00000100311
PDGFC GeneProduct ensembl:ENSG00000145431
PDGFD GeneProduct ensembl:ENSG00000170962
FGF2 GeneProduct ensembl:ENSG00000138685
GAS6 GeneProduct ensembl:ENSG00000183087
IL6 GeneProduct ensembl:ENSG00000136244
MET GeneProduct ensembl:ENSG00000105976
MET GeneProduct ensembl:ENSG00000105976
EGFR GeneProduct ensembl:ENSG00000146648
KDR GeneProduct ensembl:ENSG00000128052
PDGFRB GeneProduct ensembl:ENSG00000113721
FGFR3 GeneProduct ensembl:ENSG00000068078
JAK2 GeneProduct ensembl:ENSG00000096968
STAT3 GeneProduct ensembl:ENSG00000168610
STAT3 GeneProduct ensembl:ENSG00000168610
GAB1 GeneProduct ncbigene:2549
AKT1 GeneProduct ncbigene:207
AKT2 GeneProduct ncbigene:208
AKT3 GeneProduct ncbigene:10000
PDPK1 GeneProduct ensembl:ENSG00000140992
GSK3B GeneProduct ensembl:ENSG00000082701
BAD GeneProduct ncbigene:572
EIF4EBP1 GeneProduct ncbigene:1978
MTOR GeneProduct ncbigene:2475
FOXO3 GeneProduct ensembl:ENSG00000118689
RPS6KB1 GeneProduct ncbigene:6198
RPS6KB2 GeneProduct ncbigene:6199
BIM GeneProduct ensembl:ENSG00000153094
EIF4E2 GeneProduct ensembl:ENSG00000135930
PLCG2 GeneProduct ensembl:ENSG00000197943
PRKCB GeneProduct ensembl:ENSG00000166501
PRKCG GeneProduct ensembl:ENSG00000126583
GRB2 GeneProduct ncbigene:2885
ARAF GeneProduct ensembl:ENSG00000078061
MAP2K1 GeneProduct ncbigene:5604
MAPK1 GeneProduct ncbigene:5594
BRAF GeneProduct ncbigene:673
SOS2 GeneProduct ncbigene:6655
MAPK3 GeneProduct ncbigene:5595
SOS1 GeneProduct ensembl:ENSG00000115904
HRAS GeneProduct ensembl:ENSG00000174775
NF1 GeneProduct ensembl:ENSG00000196712
MAP2K2 GeneProduct ncbigene:5605
RAF1 GeneProduct ncbigene:5894
SHC2 GeneProduct ensembl:ENSG00000129946
SHC3 GeneProduct ensembl:ENSG00000148082
SHC4 GeneProduct ensembl:ENSG00000185634
BCL2 GeneProduct ensembl:ENSG00000171791
STAT3 GeneProduct ensembl:ENSG00000168610
PIK3CA GeneProduct ncbigene:5290
PIK3R3 GeneProduct ncbigene:8503
PIK3R1 GeneProduct ncbigene:5295
PIK3CD GeneProduct ncbigene:5293
PIK3CB GeneProduct ncbigene:5291
NRAS GeneProduct ncbigene:4893
MRAS GeneProduct ncbigene:22808
RRAS GeneProduct ensembl:ENSG00000126458
RRAS2 GeneProduct ensembl:ENSG00000133818
PIK3R2 GeneProduct ncbigene:5296


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