Overview of Overview of EGFR Signaling in Cancer

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Homology

 

Receptor tyrosine kinases (RTKs) represent the largest class of cellular receptors. The extracellular ligand-binding domain of these proteins transmit signals through its transmembrane segment to regulate critical functions such as proliferation, apoptosis, and differentiation via its intracellular tyrosine kinase domain.  The epidermal growth factor receptor (EGFR; erbB1) represents one fraction of the diverse RTK family.  Other members of the RTK family includes HER2/neu (ErbB2), erbB3, and erbB4. 1–3

 

Pathway Signaling

 

RTK family members are characterized by the variety of receptor-specific ligands and signaling pathway intermediates which promote transduction.  The specific ligands that bind to EGFR are epidermal growth factor (EGF), transforming growth factor-a (TGF-a), amphiregulin, epigen, betacellulin, heparin-binding EGF, and epieregulin.1,3–5 Following binding of either of these ligands to EGFR, the receptor forms either a homo- or heterodimeric complex activating the receptor’s tyrosine kinase domain.2,3 The enzymatic activity of EGFR phosphorylates and thereby activates intracellular proteins and regulates transcription.6   EGFR transduction is most commonly mediated by three major signaling pathways:

 

  1. The Ras-Raf-MAP kinase pathway,7
  2. The phosphatidylinositol 3-kinase (PI-3 K) and Akt pathway,8
  3. The stress-activated Jak/Stat and protein kinase C pathway.1,9

 

Pathophysiology and Therapeutics

 

In contrast to the maintenance of cellular homeostasis within normal tissue, EGFR also promotes malignant transformation and tumor growth via dysregulation of apoptosis, cellular proliferation, promotion of angiogenesis, and metastasis.  Aberrant activation of ErbB receptors are attributed to: 

 

  1. Receptor overexpression,10
  2. Mutant receptors resulting in ligand-independent activation,10,11
  3. Autocrine activation by overproduction of the ligand,12
  4. Ligand-independent activation through other receptor systems such as the urokinase plasminogen receptor.1,13

 

In regards to EGFR therapeutic targeting, these modes of aberrant activation are vulnerable to:

 

  1. Monoclonal antibodies against the EGFR,9
  2. Inhibition of the receptor tyrosine kinase domain,14
  3. Inhibition of receptor trafficking to the cell membrane,15
  4. Inhibition of EGFR synthesis through antisense oligonucleotides.16

 

Examples of tyrosine kinase inhibitors (TKIs) include erlotinib and gefitinib that reversibly inhibit the EGFR tyrosine kinase domain by competitively binding w/ATP.  The monoclonal antibodies, cetuximab (a chimeric mouse-human IgG1 ab) and panitumumab (a fully humanized IgG2 ab), block ligand binding to the extracellular domain of EGFR, promote receptor internalization, and mediate cytotoxicity. In advanced non-small cell lung cancer (NSCLC), chemotherapy results in a median overall survival (OS) of 8 to 12 months and a median progression-free survival (PFS) of 5- 6 months. 17–19   When TKIs, gefitinib or erlotinib, are used the response rates of OS and PFS increased to 20 -30 months and 10 – 14 months, respectively. 19–23

 

Despite identification of several independent therapeutic strategies, investigators have discovered an assortment of mechanisms in which EGFR is further modified to continue malignancy despite the previously described standard-of-care. Therefore, the current therapeutic outlook is increasingly dedicated to characterizing and targeting the mechanism of resistance and increasing the disease-free survival of patients.  The overall resolution thus far to such objective has been to combine classic chemotherapy, with current advanced targeted therapies as an attempt of “complete” medicine.24 .

 

 

Detection of human CD86 in FFPE tonsil by IHC. Antibody: Rabbit anti-CD86 recombinant monoclonal [BLR030F] (A700-030). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human CD86 in FFPE tonsil by IHC. Antibody: Rabbit anti-CD86 recombinant monoclonal [BLR030F] (A700-030). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human ERK5 by WB of immunoprecipitates from 293T lysate. Antibodies: Rabbit anti-ERK5 (A302-655A and A302-656A). Secondary: ReliaBLOT® reagents (WB120).

Detection of human ERK5 by WB of immunoprecipitates from 293T lysate. Antibodies: Rabbit anti-ERK5 (A302-655A and A302-656A). Secondary: ReliaBLOT® reagents (WB120).

Detection of human PTPN12 in FFPE SW 620 cell line by ICC. Antibody: Mouse monoclonal anti-PTPN12 [BL-5-2F8] (A700-007). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human PTPN12 in FFPE SW 620 cell line by ICC. Antibody: Mouse monoclonal anti-PTPN12 [BL-5-2F8] (A700-007). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

 

Below is the current list of Bethyl antibodies involved in cell division:

 

References

1.  El-Rayes BF, LoRusso PM. 2004. Targeting the epidermal growth factor receptor. Br J Cancer. Aug 2;91:418–24. doi:10.1038/sj.bjc.6601921

2. Olayioye MA, Neve RM, Lane HA, Hynes NE. 2000. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. Jul 3;19:3159–67. doi:10.1093/emboj/19.13.3159

3. Yarden Y. 2001. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. Sept;37 Suppl 4:S3-8.

4. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, et al. 2010. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. Feb;11:121–8. doi:10.1016/S1470-2045(09)70364-X

5. Chong CR, Janne PA. 2013. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. Nov;19:1389–400. doi:10.1038/nm.3388

6. Schlessinger J. 2000. Cell signaling by receptor tyrosine kinases. Cell. Oct 13;103:211–25.

7. Lewis TS, Shapiro PS, Ahn NG. 1998. Signal transduction through MAP kinase cascades. Adv Cancer Res. 74:49–139.

8. Chan TO, Rittenhouse SE, Tsichlis PN. 1999. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem. 68:965–1014. doi:10.1146/annurev.biochem.68.1.965

9. Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. 1983. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med. Dec;1(5):511–29.

10. Hirsch FR, Varella-Garcia M, Bunn PA, Di Maria MV, Veve R, Bremmes RM, Baron AE, Zeng C, Franklin WA. 2003. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. Oct 15;21:3798–807. doi:10.1200/JCO.2003.11.069

11. Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Biegel JA, Hayes RL, Wong AJ. 1995. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. Dec 1;55:5536–9.

12. Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A. 1999. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. Dec 23-30;402:884–8. doi:10.1038/47260

13. Liu D, Aguirre Ghiso J, Estrada Y, Ossowski L. 2002. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell. Jun;1:445–57.

14. Lichtner RB, Menrad A, Sommer A, Klar U, Schneider MR. 2001. Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline tyrosine kinase inhibitors. Cancer Res. Aug 1;61:5790–5.

15. Yamazaki H, Kijima H, Ohnishi Y, Abe Y, Oshika Y, Tsuchida T, Tokunaga T, Tsugu A, Ueyama Y, Tamaoki N, et al. 1998. Inhibition of tumor growth by ribozyme-mediated suppression of aberrant epidermal growth factor receptor gene expression. J Natl Cancer Inst. Apr 15;90:581–7.

16. Ciardiello F, Caputo R, Troiani T, Borriello G, Kandimalla ER, Agrawal S, Mendelsohn J, Bianco AR, Tortora G. 2001. Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit proliferation, induce apoptosis, and cooperate with cytotoxic drugs in human cancer cell lines. Int J Cancer. Jul 15;93:172–8. doi:10.1002/ijc.1335

17. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH, Eastern Cooperative Oncology Group. 2002. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. The New England Journal of Medicine. Jan 10;346(2):92–98. doi:10.1056/NEJMoa011954

18. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, et al. 2008. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. Jul 20;26(21):3543–3551. doi:10.1200/JCO.2007.15.0375

19. Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Jänne PA, Johnson BE. 2016. Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. Apr;11(4):556–565. doi:10.1016/j.jtho.2015.12.103

20. Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al. 2009. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England Journal of Medicine. Sept 3;361(10):947–957. doi:10.1056/NEJMoa0810699

21. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al. 2010. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. The New England Journal of Medicine. Jun 24;362(25):2380–2388. doi:10.1056/NEJMoa0909530

22. Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al. 2011. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The Lancet. Oncology. Aug 12;12(8):735–742. doi:10.1016/S1470-2045(11)70184-X

23. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, et al. 2012. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The Lancet. Oncology. Mar 13;13(3):239–246. doi:10.1016/S1470-2045(11)70393-X

24. Dokala A, Thakur SS. 2017. Extracellular region of epidermal growth factor receptor: a potential target for anti-EGFR drug discovery. Oncogene. Apr 27;36(17):2337–2344. doi:10.1038/onc.2016.393