Pathway EGFR Inhibitor Pathway, Pharmacodynamics

Pharmacodynamics
Model non-tissue specific cancer cell displaying genes that may be involved in the treatment using epidermal growth factor receptor specific tyrosine kinase inhibitors or monoclonal antibodies.
EGFR Inhibitor Pathway, Pharmacodynamics
egfr TK egfr Mab egfr lingands egfr left egfr plcg shc grb2 sos1 ras pi3k jak1 raf1 map3k1 stat map2k map2k2 prkc camk akt mapk mapk8 sp1 nfkb stat fos jun myc elk1
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Description

EGFR is a transmembrane tyrosine kinase receptor that plays a central role in regulating cell division and death. EGFR belongs to the HER family of receptors which comprise four related proteins (EGFR(HER1/ErbB1), ERBB2(HER2), ERBB3(HER3) and ERBB4(HER4)). The HER receptors are known to be activated by binding to different ligands, including EGF, TGFA, heparin-binding EGF-like growth factor, amphiregulin, betacellulin, and epiregulin. After a ligand binds to the extracellular domain of the receptor, the receptor forms functionally active dimers (EGFR-EGFR (homodimer) or EGFR-HER2, EGFR-HER3, EGFR-HER4 (heterodimer)). Dimerization induces the activation of the tyrosine kinase domain, which leads to autophosphorylation of the receptor on multiple tyrosine residues. This leads to recruitment of a range of adaptor proteins (such as SHC, GRB2) and activates a series of intracellular signaling cascades to affect gene transcription, which in turn results in cancer cell proliferation, reduced apoptosis, invasion and metastasis and also stimulates tumor-induced angiogenesis.

The pathways mediating downstream effects of EGFR have been well studied and three major signalling pathways have been identified. The first pathway involves RAS-RAF-MAPK pathway, where phosphorylated EGFR recruits the guanine-nucleotide exchange factor via the GRB2 and Shcadapter proteins, activating RAS and subsequently stimulating RAF and the MAP kinase pathway to affect cell proliferation, tumor invasion, and metastasis. The second pathway involves PI3K/AKT pathway, which activates the major cellular survival and anti-apoptosis signals via activating nuclear transcription factors such as NFKB. The third pathway involves JAK/STAT pathway which is also implicated in activating transcription of genes associated with cell survival. EGFR activation may also lead to phosphorylation of PLCG and subsequent hydrolysis of phosphatidylinositol 4,5 biphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), resulting in activation of protein kinase C (PRKC) and CAMK.

Given the prominent importance of EGFR signaling in cancer development, both anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors have been developed. Anti-EGFR antibodies, eg. cetuximab and panitumumab, bind to the extracellular domain of EGFR monomer and compete for receptor binding by the endogenous ligands; in this way they block ligand-induced receptor activation. The small molecule EGFR inhibitors, such as erlotinib, gefitinib and lapatinib, compete with ATP to bind the catalytic domain of the kinase which in turn inhibits EGFR autophosphorylation and downstream signaling. However, these inhibitors are known to be effective in only a small subset of patients. Mutations in the EGFR gene and possible down-stream effectors have been shown to be associated with various clinical outcomes associated with EGFR inhibitor treatments [Articles:17375033, 17285735, 15118073, 15118125].

Authors: Li Gong, Xing Jian Lou.
Citation:
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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History:
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (67)

Drugs/Drug Classes (5)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
AKT1, AKT2, AKT3 AKT1, AKT2, AKT3 PIP3 10787417, 15168354, 18473993
Ca++ Ca++ IP3
CAMK1, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G CAMK1, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G Ca++ 14671000, 16083343
EGFR, ERBB2, ERBB3, ERBB4 EGFR, ERBB2, ERBB3, ERBB4 erlotinib, gefitinib, lapatinib 18337605
JAK1 JAK1 EGFR, ERBB2, ERBB3, ERBB4 15284024
MAP2K1 MAP2K1 RAF1 12843393, 18337605
MAP2K7 MAP2K7 MAP3K1 18713996
MAP3K1 MAP3K1 GRB2, HRAS, KRAS, MRAS, NRAS, RRAS, SHC1, SHC2, SHC3, SOS1 18713996
MAPK1, MAPK3 MAPK1, MAPK3 MAP2K1 12843393, 18337605
MAPK8 MAPK8 MAP2K7 18713996
PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3 PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3 EGFR, ERBB2, ERBB3, ERBB4 16377102, 8550620
PIP2 PIP2 PLCG1, PLCG2
PIP3 PIP3 PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3
PLCG1, PLCG2 PLCG1, PLCG2 EGFR, ERBB2, ERBB3, ERBB4 14500405
PRKCA, PRKCB, PRKCG PRKCA, PRKCB, PRKCG DAG 10327068
RAF1 RAF1 GRB2, HRAS, KRAS, MRAS, NRAS, RRAS, SHC1, SHC2, SHC3, SOS1 12843393, 18337605, 9405464
GRB2, HRAS, KRAS, MRAS, NRAS, RRAS, SHC1, SHC2, SHC3, SOS1 GRB2, HRAS, KRAS, MRAS, NRAS, RRAS, SHC1, SHC2, SHC3, SOS1 EGFR 12648466, 16377102
STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B JAK1 15284024
ELK1, FOS, JUN, MYC, NFKB1, NFKB2, RELA, SP1, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B ELK1, FOS, JUN, MYC, NFKB1, NFKB2, RELA, SP1, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B AKT1, AKT2, AKT3, CAMK1, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G, MAPK1, MAPK3, MAPK8, PRKCA, PRKCB, PRKCG, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B 18337605, 18519641
AREG, BTC, EGF, EREG, HBEGF, NRG1, NRG2, NRG3, TGFA EGFR, ERBB2, ERBB3, ERBB4 15238978, 17999740, 18271917, 18337605
AREG, BTC, EGF, EREG, HBEGF, NRG1, NRG2, NRG3, TGFA EGFR cetuximab, panitumumab 15238978, 18271917, 18337605
PIP2 DAG, IP3

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