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

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Predictive Biomarkers in Oncology

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Abstract

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.

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Abbreviations

4E-BPs:

eIF-4E-binding proteins

ADC:

Antibody-drug conjugate

AP-1:

Activator protein-1

AR:

Amphiregulin

BBB:

Blood-brain barrier

BTC:

Betacellulin

CAR-T:

Chimeric antigen receptor T cells

CEP17:

HER2/neu-to-chromosome 17 centromere

CR:

Complete response

CR:

Cysteine-rich domain

DAG:

Diacylglycerol

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EP:

Epigen

ErbB:

Avian erythroblastosis oncogene B

ERK:

Extracellular signal-regulated kinases

FFPET:

Formalin-fixed, paraffin-embedded tissue

FISH:

Fluorescent in situ hybridization

Grb2:

Growth factor receptor-bound protein 2

HB-EGF:

Heparin-binding EGF

HER:

Human epidermal growth factor receptor

IHC:

Immunohistochemistry

JAK:

Janus kinase

L:

Large EGF-binding domain

MAPK:

Mitogen-activated protein kinase

mCRC:

Metastatic colorectal cancer

mTOR:

Mammalian target of rapamycin

NRG:

Neuregulins

NSCLC:

Non-small cell lung cancer

ORR:

Objective response rate

OS:

Overall survival

p70S6K:

p70 ribosomal S6 kinase

PH:

Pleckstrin-homology

PI3K:

Phosphatidylinositol 3-kinase

PIP3:

Phosphatidylinositol (3,4,5) trisphosphate

PKB:

Protein kinase B

PKC:

Protein kinase C

PLC:

Phospholipase C

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

Raf:

Rapidly accelerated fibrosarcoma

Ras:

Rat sarcoma

RTKs:

Receptor tyrosine kinases

scFv:

Single-chain variable fragment

Shc2:

Src homology 2

SHP:

SH2 domain-containing inositol 5′-phosphatase

SOS:

Son of sevenless

SRS:

Stereotactic radiosurgery

STAT:

Signal transducer and activator of transcription

T-DM1:

Ado-trastuzumab emtansine

TGF-α:

Transforming growth factor-α

TKI:

Tyrosine kinase inhibitor

WBRT:

Whole brain radiation therapy

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Acknowledgments

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

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Authors and Affiliations

  1. Department of Pathology and Lab Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Zheng Cai, Payal Grover, Zhiqiang Zhu & Hongtao Zhang

  2. Department of Pathology and Laboratory Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Mark I. Greene

Authors
  1. Zheng Cai
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  2. Payal Grover
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  3. Zhiqiang Zhu
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  4. Mark I. Greene
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  5. Hongtao Zhang
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Corresponding author

Correspondence to Hongtao Zhang .

Editor information

Editors and Affiliations

  1. Department of Pathology and Lab Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Sunil Badve

  2. Targos Inc., Issaquah, WA, USA

    George Louis Kumar

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Cai, Z., Grover, P., Zhu, Z., Greene, M.I., Zhang, H. (2019). Signaling of the ErbB Receptor Family in Carcinogenesis and the Development of Targeted Therapies. In: Badve, S., Kumar, G. (eds) Predictive Biomarkers in Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-95228-4_18

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  • DOI: https://doi.org/10.1007/978-3-319-95228-4_18

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