EGFR

Epidermal growth factor receptor (EGFR), its family members Her-2/ErbB-2, Her-3, Her-4 and their ligands, are involved in over 70% of all cancers. EGFR itself has been implicated in ~30% of all solid human tumors. EGFR is associated not only with the proliferation of tumor cells, but also with enhanced tumor cell survival, angiogenesis and metastatic spread. The enhanced activity of the EGFR due to over-expression, co-expression of the receptor and its ligands, as well as activating mutations is the hallmark of many human carcinomas.

The co-expression of the EGFR and its ligands, especially TGFα and EGF, plays a key role in EGFR-mediated tumorigenesis. EGFR expression is a prognostic indicator, predicting poor survival and indicating an advanced state of the disease. When EGFR is co-expressed with other members of the Her family, the various combinations of Her dimers confer different degrees of malignancy. It has been noted that the co-expression of EGFR with Her-2 and Her-3 is associated with more aggressive clinical behavior. In many types of tumor, including lung, breast, prostate, ovary, gastrointestinal tract and brain, the EGFR receptor is expressed approximately 100 times the normal number of EGF receptors found on the surface of normal cells. Furthermore, expression of high levels of these two receptors in nonmalignant cell lines, either alone or in combination, leads to a transformed phenotype.

Due to all these observations, it is no surprise that EGFR and Her-2/Erb-2 were identified early on as important targets for drug development. Indeed, the first signal transduction therapeutic agent introduced into the clinic was Herceptin, an anti-Her-2 antibody, followed closely by the protein tyrosine kinase inhibitors Iressa (ZD 1839) and Tarceva (OSI-774) and the anti-EGFR antibody Erbitux (mAb 225).

The enhanced activity of the EGFR is due to a number of molecular events. Most common is the overexpression of the receptor along with the expression of the EGFR receptor ligands like TGFα, EGF, amphiregulin and HB-EGF, leading to persistent autocrine stimulation. Another common occurrence is an activating mutation resulting from deletion of exons 2 through 7, leading to a persistently active receptor Δ (2-7)EGFR (also known as EFFRvIII) in the absence of a ligand. The emergence of this mutation occurs in the most aggressive forms of EGFR overexpressing tumors.

Activation of the EGFR pathway is not limited to members of the EGFR family, but frequently occurs due to the transactivation by other signaling pathways such as mitogenic G protein-coupled receptors and the PDGF receptor. Furthermore, the EGFR pathway cooperates in a synergistic manner with pp60^c-Src, and the deletion of PTEN, the negative regulator of PKB/Akt. The frequent involvement of EGFR in human tumors has identified it as a target for novel therapies. The first breakthrough was the development of selective EGFR kinase inhibitors (tyrphostins) like tyrphostins, AG 1478 and ZD 1839 (Iressa). Iressa is one of the two kinase inhibitors (the other being Gleevec) to receive approval for clinical application. It is important to note that it was recently found that the response of patients suffering from non-small-cell lung carcinoma to Iressa, is limited to the 7-10% harboring mutations in the kinase domain of the receptor. Other inhibitors, similar to Iressa, like Tarceva (OSI-774), the pan-Her reversible inhibitor GW 2016, the irreversible inhibitor CI-1033, which targets both RGFR and Her-2, are in the pipeline. Antibodies to the EGFR, like Erbitux and TGFα fused to a mutated form of pseudomonas exotoxin, TP-38, have also undergone clinical development.

The Table below contains accepted modulators and additional information. 

Family Members	EGFR	ErbB2
Other Names	ErbB-1 (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog) HER1 ERBB crbB	Neu (rat) HER2
Molecular Weight	~180 kDa	~185 kDa
Structural Data	1210 aa	1255 aa
Isoforms	Four alternatively spliced transcripts Secreted extracellular domain Auto-activating deletions in the extracellular domain	Two alternatively spliced transcripts Secreted form (Herstatin)
Species	All four receptors are expressed in mammals. A single ortholog of the receptor is expressed in D. melanogaster and C. elegans
Domain Organization	All four receptors have similar structural domains comprising of an extracellular ligand binding domain, a single transmembrane domain, an intracellular tyrosine kinase domain and a large unstructured tail
Phosphorylation Sites	Tyr845 Tyr891 Tyr920 Tyr974 Tyr992 Tyr1045 Tyr1068 Tyr1045 Tyr1086 Tyr1101 Tyr1114 Tyr1148 Tyr1173 Tyr654 Tyr669 Ser1046 Ser1047	Tyr882 Tyr 899 Tyr958 Tyr1023 Tyr1028 Tyr1139 Tyr1143 Tyr1196 Tyr1221/22 Tyr1226 Tyr1227 Tyr1249 Tyr1253
Tissue Distribution	Brain, neurons, skeletal muscle, prostate, liver, pancreas, lung, tongue, skin, kidney, trachea	Brain, spinal cord, placenta, prostate, heart, liver, lung, kidney, pancreas
Subcellular Localization	Not Known	Not Known
Binding Partners/ Associated Proteins	EGF (E9644)	Neuregulin-1
Upstream Activators	Epidermal growth factor (EGF) (E9644) Transforming growth factor-α (TGF-α) (T7924) Amphiregulin (AR) (A7080) Heparin binding-EGF (HB-EGF) (SRP3052) Betacellulin (BTC) (B3670) Epiregulin (EPR) (E8780) Epigen (EPG) (SRP4969)	Does not bind any of the known EGF like ligands
Downstream Activation	Grb-2-SOS Shc Shp1 c-Src Gab1 PLC-γ PKC c-Cbl	Grb-2-SOS Shc
Activators	Not Known	Not Known
Inhibitors	Gefitinib Erlotinib EKB-569 GW572016 PKI-166 AEE-788 CI-1033 (C7249) AG1478 (T4182)	TAK-165 GW572016 AEE-788 CI-1033 (C7249) PKI-166
Selective Activators	Not Known	Not Known
Physiological Function	Receptor for EGF; involved in control of cell growth and differentiation	Essential component of a neuregulin-receptor complex
Disease Relevance	Glioblastoma, malignant neoplasms and carcinomas including adenocarcinomas of the breast, lung, prostate, pancreas, head and neck, colon, ovary, bladder	Hyperplasias, benign and malignant, neoplasms and carcinomas, including adenocarcinomas of the breast, prostate, lung, stomach, bladder, colon, cervix

Family Members	ErbB3	ErbB4
Other Names	HER3	HER4
Molecular Weight	~190 kDa	~180 kDa
Structural Data	1342 aa	1308 aa
Isoforms	Two alternatively spliced transcripts	Two alternatively spliced transcripts called HER4 JM-α and HER4 JM-β
Species	All four receptors are expressed in mammals. A single ortholog of the receptor is expressed in D. melanogaster and C. elegans
Domain Organization	All four receptors have similar structural domains comprising of an extracellular ligand binding domain, a single transmembrane domain, an intracellular tyrosine kinase domain and a large unstructured tail
Phosphorylation Sites	Has an impaired kinase and cannot autophosphorylate Tyr1035 Tyr1178 Tyr1180 Tyr1203/5 Tyr1241 Tyr1243 Tyr1257 Tyr1270 Tyr1309	Tyr1066 Tyr1162 Tyr1066 Tyr1188 Tyr1189 Tyr1242 Tyr1258 Tyr1284
Tissue Distribution	Brain, prostate, dorsal root ganglion, liver, placenta, salivary gland, spinal cord, uterus, heart, lung, muscle, pituitary, thyroid, pancreas, kidney	Brain, bone marrow, spinal cord, dorsal root ganglion, testis, liver, skeletal muscle, cardiac myocytes, salivary gland, tongue, skin, trachea, pancreas
Subcellular Localization	Not Known	Not Known
Binding Partners/ Associated Proteins	Neuregulin Ebp1 SH2 domain of p85	Neuregulin-1 β-cellulin
Upstream Activators	α and β isoforms of Heregulin-1/Neuregulin-1 (HRG/NRG-1α, HRG/NRG-1β) α and β isoforms of Heregulin-2/ Neuregulin-2 (HRG/NRG-2α, HRG/NRG-2β)	Betacellulin (BTC) (B3670) Heparin binding- EGF (HB-EGF) (SRP3052) Epiregulin (EPR) (E8780) Neuregulin-3 (NRG-3) Neuregulin-4 (NRG-4)
Downstream Activation	Grb-2/7-SOS Shc PI3K (P8615)	Shc Grb-2-SOS PI3K (P8615)
Activators	Not Known	Not Known
Inhibitors	Not Known	AEE-788 CI-1033 (C7249)
Selective Activators	Not Known	Not Known
Physiological Function	Involved in development of variety of tissues	Interacts with neuregulins NRG-2 NRG-3 Heparin-binding EGF-like growth factor
Disease Relevance	Malignant neoplasms of the breast, ovary, pancreas, lung, prostate, bladder, colon	Role of ErbB4 in malignancies is not well established. However, it has been implicated in some tumors of the breast, prostate, ovary, brain, lung

References

1. Alroy I, Yarden Y. 1997. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. 410(1):83-86. https://doi.org/10.1016/s0014-5793(97)00412-2

2. Bartolotti M, Franceschi E, Brandes AA. 2012. EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer. Expert Review of Anticancer Therapy. 12(11):1429-1435. https://doi.org/10.1586/era.12.121

3. Blagosklonny MV. 2004. Gefitinib (Iressa) in Oncogene-Addictive Cancers and Therapy for Common Cancers. Cancer Biology & Therapy. 3(5):436-440. https://doi.org/10.4161/cbt.3.5.984

4. Grünwald V, Hidalgo M. 2003. Development of The Epidermal Growth Factor Receptor Inhibitor Tarcevatm(Osi-774).235-246. https://doi.org/10.1007/978-1-4615-0081-0_19

5. He H, Levitzki A, Zhu H, Walker F, Burgess A, Maruta H. 2001. Platelet-derived Growth Factor Requires Epidermal Growth Factor Receptor to Activate p21-activated Kinase Family Kinases. J. Biol. Chem.. 276(29):26741-26744. https://doi.org/10.1074/jbc.c100229200

6. Huang HS, Nagane M, Klingbeil CK, Lin H, Nishikawa R, Ji X, Huang C, Gill GN, Wiley HS, Cavenee WK. 1997. The Enhanced Tumorigenic Activity of a Mutant Epidermal Growth Factor Receptor Common in Human Cancers Is Mediated by Threshold Levels of Constitutive Tyrosine Phosphorylation and Unattenuated Signaling. J. Biol. Chem.. 272(5):2927-2935. https://doi.org/10.1074/jbc.272.5.2927

7. Jamal-Hanjani M, Spicer J. 2012. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Metastatic to the Brain. Clinical Cancer Research. 18(4):938-944. https://doi.org/10.1158/1078-0432.ccr-11-2529

8. Kim T, Murren J. 2002. Erlotinib OSI/Roche/Genentech. Curr. Opin. Investig.. Drugs(3):1385-1395.

9. Leserer, Andreas Gschwind, Axel Ull M. 2000. Epidermal Growth Factor Receptor Signal Transactivation. IUBMB Life (International Union of Biochemistry and Molecular Biology: Life). 49(5):405-409. https://doi.org/10.1080/152165400410254

10. Levitzki A, Gazit A. 1995. Tyrosine kinase inhibition: an approach to drug development. Science. 267(5205):1782-1788. https://doi.org/10.1126/science.7892601

11. Mendelsohn J. 2001. The epidermal growth factor receptor as a target for cancer therapy..3-9. https://doi.org/10.1677/erc.0.0080003

12. Nakata A, Gotoh N. 2012. Recent understanding of the molecular mechanisms for the efficacy and resistance of EGF receptor-specific tyrosine kinase inhibitors in non-small cell lung cancer. Expert Opinion on Therapeutic Targets. 16(8):771-781. https://doi.org/10.1517/14728222.2012.697155

13. Norman P. 2002. ZD-1839 (AstraZeneca). Curr. Opin. Investig. Drugs. 2428-434.

14. Okines A, Cunningham D, Chau I. 2011. Targeting the human EGFR family in esophagogastric cancer. Nat Rev Clin Oncol. 8(8):492-503. https://doi.org/10.1038/nrclinonc.2011.45

15. Osherov N, Levitzki A. 1994. Epidermal-Growth-Factor-Dependent Activation of the Src-Family Kinases. Eur J Biochem. 225(3):1047-1053. https://doi.org/10.1111/j.1432-1033.1994.1047b.x

16. Settleman J. 2004. Inhibition of Mutant EGF Receptors by Gefitinib: Targeting an Achilles? Heel of Lung Cancer. Cell Cycle. 3(12):1496-1497. https://doi.org/10.4161/cc.3.12.1325

17. Sgambato A, Casaluce F, Maione P, Rossi A, Rossi E, Napolitano A, Palazzolo G, A. Bareschino M, Schettino C, C. Sacco P, et al. 2012. The Role of EGFR Tyrosine Kinase Inhibitors in the First-Line Treatment of Advanced Non Small Cell Lung Cancer Patients Harboring EGFR Mutation. curr med chem. 19(20):3337-3352. https://doi.org/10.2174/092986712801215973

18. Uitdehaag JC, Verkaar F, Alwan H, de Man J, Buijsman RC, Zaman GJ. 2012. A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets. 166(3):858-876. https://doi.org/10.1111/j.1476-5381.2012.01859.x