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  • Review Article
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Novel anticancer targets: revisiting ERBB2 and discovering ERBB3

Nature Reviews Cancer volume 9, pages 463–475 (2009)Cite this article

Key Points

  • The Erbb family consists of four closely related type 1 transmembrane tyrosine kinase receptors: the epidermal growth factor receptor (EGFR; also known as ERBB1), ERBB2, ERBB3 and ERBB4. Signalling through the Erbb family underpins many of the cellular activities on which cell survival and function depend.

  • EGFR, ERBB2 and ERBB3 are all implicated in the development and progression of cancer, and heterodimerization of the receptors plays a crucial part in their function. The role of ERBB4 in oncogenesis is less clear and this receptor might be involved in inhibition of cell growth rather than proliferation.

  • Aberrant ERBB2 expression or function has been implicated in the evolution of both breast and gastric cancers and is evident in other cancer types, including ovarian and salivary gland tumours. This receptor has proved to be a potent target for anticancer therapies, including antibody-based therapies to prevent ligand binding, dimer formation or antibody-dependent cell-mediated cytotoxicity, and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners.

  • New strategies against ERBB2 include Erbb tyrosine kinase inhibitors, heat shock protein 90 inhibitors, Erbb dimerization inhibitors and antibody–chemotherapy conjugates. All of these approaches have shown substantial clinical activity in patients who have progressed on trastuzumab, an anti-ERBB2 monoclonal antibody.

  • The extent of the role of ERBB3 is now emerging and considerable research efforts are focused on developing new therapies that target ERBB3.

  • ERBB3-specific monoclonal antibodies are now under evaluation, and data suggest that individual tyrosine kinase inhibitors might inhibit ERBB3 activation or its interaction with downstream signalling components.

  • Preventing the dimerization of ERBB3 with its signalling partners, in particular ERBB2 with which it forms the most potent mitogenic signalling dimer, might offer an effective method of preventing oncogenic signalling across the Erbb network.

Abstract

Aberrant receptor expression or functioning of the epidermal growth factor receptor (Erbb) family plays a crucial part in the development and evolution of cancer. Inhibiting the signalling activity of individual receptors in this family has advanced the treatment of a range of human cancers. In this Review we re-evaluate the role of two important family members, ERBB2 (also known as HER2) and ERBB3 (also known as HER3), and explore the mechanisms of action and preclinical and clinical data for new therapies that target signalling through these pivotal receptors. These new therapies include tyrosine kinase inhibitors, antibody–chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2–ERBB3 dimers.

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Figure 1: Erbb receptors.
Figure 2: ERBB3 plays a central part in oncogenic signalling.
Figure 3: Potential ERBB2 targets for anticancer therapy.

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Acknowledgements

Support for third-party writing assistance for this manuscript was provided by Genentech USA.

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Authors and Affiliations

  1. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119–129, Barcelona, 08035, Spain

    José Baselga

  2. Washington Cancer Institute, Washington Hospital Center, 110 Irving Street, NW, Washington, 20010, DC, USA

    Sandra M. Swain

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Correspondence to José Baselga.

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Competing interests

José Baselga has a consultant/advisory role for Roche, Infinity, Novartis and Exelixis. He receives research funding from GlaxoSmithKline.

Sandra M. Swain is an (unpaid) advisor for GNE and Sanofi-Aventis and has travelled for Sanofi-Aventis. She receives research funding from BMS and GNE.

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DATABASES

CenterWatch Clinical Trials 

BO17929

ClinicalTrials.gov 

NCT00490139

NCT00545688

NCT00553358

NCT00567190

National Cancer Institute Drug Dictionary 

BIBW-2992

capecitabine

cetuximab

ertumaxomab

gefitinib

lapatinib

neratinib

pertuzumab

tanespimycin

trastuzumab

FURTHER INFORMATION

Vall d'Hebron Institute of Oncology homepage

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Glossary

Overall survival

The total length of time from a particular point, such as diagnosis or initiation of treatment, until the patient succumbs to disease.

Clinical benefit rate

A metric that combines the proportion of patients who achieve any response or stable disease.

Overall response rate

Also known as the objective response rate.The proportion of patients who achieve either a complete or partial response to treatment.

Progression-free survival

The total length of time during and after treatment in which the disease does not get worse.

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Baselga, J., Swain, S. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer 9, 463–475 (2009). https://doi.org/10.1038/nrc2656

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