New insights into ErbB3 function and therapeutic targeting in cancer

ABSTRACT

Introduction

The importance of ErbB3 receptor tyrosine kinase in cancer progression, primary and acquired drug resistance, has become steadily evident since its discovery in 1989. ErbB3 overexpression in various solid organ malignancies is associated with shorter survival of patients. However, initial strategies to therapeutically target ErbB3 have not been rewarding.

Areas covered

Here, we provide an overview of ErbB3 biology in carcinogenesis. We outline the role of ErbB3 as a critical pathway for resistance to other anti-cancer drugs. We focus on emerging clinical data, which will steer the potential future development of ErbB3 directed therapies.

Expert opinion

Initial approaches to ErbB3 targeting have been challenging. However, the lack of success of anti-ErbB3 therapies in ongoing clinical trials may relate more to the complex biology of the receptor and challenges with the biomarkers used to date. Furthermore, it seems certain that the expression of the receptor per se is necessary but not sufficient for the response to ErbB3 therapies. Emerging data suggest that more sophisticated biomarkers are needed. Nonetheless, it is also likely that ErbB3 therapies may have the most efficacy in combination therapy, and their favorable toxicity profile makes this feasible.

KEYWORDS:

• ErbB3
• ErbB3 overexpression
• ErbB3 amplification
• ErbB3 mutations
• anti-ErbB3 therapies
• anti-ErbB3 antibodies
• monoclonal antibodies
• receptor tyrosine kinase

Article highlights

• ErbB3 is overexpressed in various cancers and plays a significant role in cancer progression, primary and acquired drug resistance. Not surprisingly, ErbB3 overexpression is associated with shorter survival of patients with head and neck, lung, breast, gastric, gall bladder, pancreatic, colorectal, melanoma, prostate, and ovarian cancer.

• It is difficult to ascertain the accurate incidence of ErbB3 mutations, overexpression, and amplification, as they are not routinely tested in clinical practice. Specifically, more work is required to define ErbB3 expression and amplification using robust and reproducible approaches.

• Over the years, less attention has been paid to the role of ErbB3 in carcinogenesis, and current strategies to target ErbB3 have not been rewarding. The lack of fully predictive biomarkers to identify the selective patient population remains a significant barrier for the success of anti-ErbB3 therapies in ongoing clinical trials. At present, there is no approved anti-ErbB3 therapy in clinical practice.

• Antibodies that are tumor-specific, harbor a unique mechanism of action and that synchronously target ErbB3 and its oncogenic dimerization partners hold promise to combat ErbB3 activity effectively.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

U Hafeez is supported by a scholarship from La Trobe University. AM Scott is supported by a Senior Investigator Fellowship from National Health and Medical Research Council of Australia [No. 1177837]. This work was supported in part by NHMRC [Grant No. 1092788], and the Operational Infrastructure Support Program provided by the Victorian Government.