Signaling of the ErbB Receptor Family in Carcinogenesis and the Development of Targeted Therapies

  • Zheng Cai
  • Payal Grover
  • Zhiqiang Zhu
  • Mark I. Greene
  • Hongtao ZhangEmail author


The epidermal growth factor receptor (EGFR) family of tyrosine kinases (RTKs) plays several crucial roles in the proliferation of many types of cells—notably epithelial—and many other cells as well as in the pathogenesis and progression of a variety of carcinomas. Activation of the ErbB receptors, either by their ligand or by genetic amplification or mutations, has been associated with many aspects of transformation. As a result, many therapeutic agents have been developed which target distinct receptors or receptor complexes within this family. Currently, therapeutic drugs specifically targeting ErbB receptors have been approved for colorectal, head and neck, lung, breast, esophageal, gastric, and pancreatic cancers. Herein, we review the discovery of the ErbB receptors, signaling pathways by activated receptors, and clinical application of ErbB inhibitors. Also discussed are the challenges for the still-developing future of ErbB inhibitors.


EGFR HER2 ErbB Receptor tyrosine kinase Targeted therapy Antibody Tyrosine kinase inhibitor (TKI) Antibody-drug conjugate (ADC) 



eIF-4E-binding proteins


Antibody-drug conjugate


Activator protein-1




Blood-brain barrier




Chimeric antigen receptor T cells


HER2/neu-to-chromosome 17 centromere


Complete response


Cysteine-rich domain




Epidermal growth factor


Epidermal growth factor receptor




Avian erythroblastosis oncogene B


Extracellular signal-regulated kinases


Formalin-fixed, paraffin-embedded tissue


Fluorescent in situ hybridization


Growth factor receptor-bound protein 2


Heparin-binding EGF


Human epidermal growth factor receptor




Janus kinase


Large EGF-binding domain


Mitogen-activated protein kinase


Metastatic colorectal cancer


Mammalian target of rapamycin




Non-small cell lung cancer


Objective response rate


Overall survival


p70 ribosomal S6 kinase




Phosphatidylinositol 3-kinase


Phosphatidylinositol (3,4,5) trisphosphate


Protein kinase B


Protein kinase C


Phospholipase C


Phosphatase and tensin homolog deleted on chromosome 10


Rapidly accelerated fibrosarcoma


Rat sarcoma


Receptor tyrosine kinases


Single-chain variable fragment


Src homology 2


SH2 domain-containing inositol 5′-phosphatase


Son of sevenless


Stereotactic radiosurgery


Signal transducer and activator of transcription


Ado-trastuzumab emtansine


Transforming growth factor-α


Tyrosine kinase inhibitor


Whole brain radiation therapy



This work was supported by grants from the Breast Cancer Research Foundation and the National Institutes of Health to M.I.G. (R01CA089481, R01CA149425).


  1. 1.
    Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984;307(5951):521–7. PubMed PMID: 6320011.CrossRefPubMedGoogle Scholar
  2. 2.
    Drebin JA, Shilo BZ, Weinberg RA, Greene MI. Preliminary evidence of an association between an activated cellular transforming gene and a tumor specific transplantation antigen. In: Vitetta E, editor. ICN-UCLA Symposia. New York: Academic Press; 1982.Google Scholar
  3. 3.
    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, Greene MI. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest. 2007;117(8):2051–8. Epub 2007/08/03. PubMed PMID: 17671639; PMCID: 1934579.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Qian X, LeVea CM, Freeman JK, Dougall WC, Greene MI. Heterodimerization of epidermal growth factor receptor and wild-type or kinase-deficient Neu: a mechanism of interreceptor kinase activation and transphosphorylation. Proc Natl Acad Sci U S A. 1994;91(4):1500–4.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nyati MK, Morgan MA, Feng FY, Lawrence TS. Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer. 2006;6(11):876–85. Scholar
  7. 7.
    Drebin JA, Link VC, Greene MI. Monoclonal antibodies specific for the neu oncogene product directly mediate anti-tumor effects in vivo. Oncogene. 1988;2(4):387–94. Epub 1988/04/01. PubMed PMID: 2896329.PubMedGoogle Scholar
  8. 8.
    Cai Z, Zhang G, Zhou Z, Bembas K, Drebin JA, Greene MI, Zhang H. Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes. Oncogene 2008;27(27):3870–4. Epub 2008/02/12. PubMed PMID: 18264138; PMCID: 2819401.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2003;21(14):2787–99. Epub 2003/07/16. PubMed PMID: 12860957.CrossRefPubMedGoogle Scholar
  10. 10.
    Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105(6):2070–5. Epub 2008/01/30. PubMed PMID: 18227510; PMCID: 2538882.CrossRefGoogle Scholar
  11. 11.
    Lin NU, Eierman W, Greil R, Campone M, Kaufman B, Steplewski K, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neuro-Oncol. 2011;105(3):613–20. Scholar
  12. 12.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013. PubMed PMID: 24101045.CrossRefPubMedGoogle Scholar
  13. 13.
    Lam L, Czerniecki BJ, Fitzpatrick E, Xu S, Schuchter L, Xu X, Zhang H. Interference-free HER2 ECD as a serum biomarker in breast cancer. J Mol Biomark Diagn 2014;4(3):151. Epub 2014/08/05. PubMed PMID: 25089226; PMCID: 4114390.
  14. 14.
    Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97(9):643–55. PubMed PMID: 15870435.CrossRefPubMedGoogle Scholar
  15. 15.
    Keith KC, Lee Y, Ewend MG, Zagar TM, Anders CK. Activity of Trastuzumab-Emtansine (Tdm1) in Her2-positive breast cancer brain metastases: a case series. Cancer Treat Commun 2016;7:43–6. PubMed PMID: 27114895; PMCID: PMC4840897.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Baik CS, Chamberlain MC, Chow LQ. Targeted therapy for brain metastases in EGFR-mutated and ALK-rearranged non-small-cell lung cancer. J Thorac Oncol. 2015;10(9):1268–78. PubMed PMID: 26107553.CrossRefPubMedGoogle Scholar
  17. 17.
    Freedman RA, Gelman RS, Wefel JS, Melisko ME, Hess KR, Connolly RM, et al. Translational breast cancer research consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2016;34(9):945–52. PubMed PMID: 26834058; PMCID: PMC5070554 online at Author contributions are found at the end of this article.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zeng Q, Wang J, Cheng Z, Chen K, Johnstrom P, Varnas K, et al. Discovery and evaluation of clinical candidate AZD3759, a potent, oral active, central nervous system-penetrant, epidermal growth factor receptor tyrosine kinase inhibitor. J Med Chem. 2015;58(20):8200–15. PubMed PMID: 26313252.CrossRefPubMedGoogle Scholar
  19. 19.
    Berghoff AS, Bago-Horvath Z, Dubsky P, Rudas M, Pluschnig U, Wiltschke C, et al. Impact of HER-2-targeted therapy on overall survival in patients with HER-2 positive metastatic breast cancer. Breast J. 2013;19(2):149–55. Epub 2013/01/29. Scholar
  20. 20.
    Merry CR, McMahon S, Forrest ME, Bartels CF, Saiakhova A, Bartel CA, et al. Transcriptome-wide identification of mRNAs and lincRNAs associated with trastuzumab-resistance in HER2-positive breast cancer. Oncotarget. 2016;7(33):53230–44. PubMed PMID: 27449296; PMCID: PMC5288181.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Park S, Jiang Z, Mortenson ED, Deng L, Radkevich-Brown O, Yang X, Sattar H, Wang Y, Brown NK, Greene M, Liu Y, Tang J, Wang S, Fu YX. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 2010;18(2):160–70. Epub 2010/08/17. PubMed PMID: 20708157; PMCID: 2923645.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bianchini G, Gianni L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol. 2014;15(2):e58–68. Epub 2014/02/01. PubMed PMID: 24480556.CrossRefPubMedGoogle Scholar
  23. 23.
    Nagai Y, Tsuchiya H, Runkle EA, Young PD, Ji MQ, Norton L, Drebin JA, Zhang H, Greene MI. Disabling of the erbB pathway followed by IFN-gamma modifies phenotype and enhances genotoxic eradication of breast tumors. Cell Rep 2015;12(12):2049–59. Epub 2015/09/15. PubMed PMID: 26365188; PMCID: PMC4591220.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhang H, Lam L, Nagai Y, Zhu Z, Chen X, Ji MQ, Greene MI. A targeted immunotherapy approach for HER2/neu transformed tumors by coupling an engineered effector domain with interferon-γ. Oncoimmunology. 2018;7(4):e1300739. PMCID:PMC5889208.CrossRefPubMedGoogle Scholar
  25. 25.
    Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T, Zhang H, Palakurthi S, Jang J, Lelais G, DiDonato M, Bursulaya B, Michellys PY, Epple R, Marsilje TH, McNeill M, Lu W, Harris J, Bender S, Wong KK, Janne PA, Eck MJ. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534(7605):129–32. PubMed PMID: 27251290; PMCID: PMC4929832.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Newick K, O'Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annu Rev Med. 2017;68:139–52. PubMed PMID: 27860544.CrossRefPubMedGoogle Scholar
  27. 27.
    Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, et al. Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;33(15):1688–96. PubMed PMID: 25800760; PMCID: PMC4429176.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–51. PubMed PMID: 20179677; PMCID: PMC2862534.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 2015;75(17):3596–607. PubMed PMID: 26330166; PMCID: PMC4560113.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Feng K, Guo Y, Dai H, Wang Y, Li X, Jia H, et al. Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. Sci China Life Sci. 2016;59(5):468–79. Scholar
  31. 31.
    Karp DD, Falchook GS, editors. Handbook of targeted cancer therapy. Philadelphia, PA: Wolters Kluwer; 2015.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Zheng Cai
    • 1
  • Payal Grover
    • 1
  • Zhiqiang Zhu
    • 1
  • Mark I. Greene
    • 2
  • Hongtao Zhang
    • 1
    Email author
  1. 1.Department of Pathology and Lab MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Pathology and Laboratory MedicineThe Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA

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