Prognostic significance and targeting of HER family in colorectal cancer 

Abstract

Colorectal cancer is one of the leading causes of cancer deaths. At present, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) cetuximab and panitumumab and anti-vascular endothelial growth factor (VEGF) mAb bevacizumab have been incorporated into treatment paradigms for patients with refractory metastatic colorectal cancer. However, many patients simply do not respond to these treatments or eventually acquire resistance following a short course therapy. In this article, we review the literature for studies on the expression patterns, prognostic significance and predictive value of HER (also called erbB) family members and other factors for response to therapy with the HER inhibitors in colorectal cancer. We discuss some of the advances, challenges as well as future opportunities for more effective targeting of the HER receptors using a cocktail of HER inhibitors (e.g. dual and pan HER TKIs, monospecific or bispecific antibodies) in combination with other therapeutic interventions.

The impact of co-expression of wild-type EGFR and its ligands determined by immunohistochemistry for response to treatment with cetuximab in patients with metastatic colorectal cancer

“…Several studies have examined the mRNA expression levels of EGFR ligands and have found an association between the expression level of epiregulin, amphiregulin and TGFα and response to treatment with cetuximab [3, 18, 19, 24, 44, 45]. However, the increased expressed level of these genes may not always be translated into the corresponding proteins, which are directly competing with antibodies to bind on the EGFR on tumour cells.…”

“…In 2016, colorectal cancer is estimated to be the third most commonly diagnosed cancer (134,900) and the third leading cause of cancer deaths (49,190) in the USA [2], highlighting the need for developing more effective and less toxic therapeutic agents. In the last three decades, the aberrant expression of the epidermal growth factor receptor (EGFR) has been reported in a wide range of tumours including colorectal, head and neck and lung cancers and the EGFR is currently an important therapeutic target for targeted therapy with anti-EGFR antibodies in such patients [3]. While treatment with a combination of antibodies and cytotoxic drugs improves response rate and median time to progression in some colorectal cancer patients, the duration of response is often limited in most patients with an advanced stage of the disease [3].…”

“…In the last three decades, the aberrant expression of the epidermal growth factor receptor (EGFR) has been reported in a wide range of tumours including colorectal, head and neck and lung cancers and the EGFR is currently an important therapeutic target for targeted therapy with anti-EGFR antibodies in such patients [3]. While treatment with a combination of antibodies and cytotoxic drugs improves response rate and median time to progression in some colorectal cancer patients, the duration of response is often limited in most patients with an advanced stage of the disease [3]. To date, of the anti-EGFR monoclonal antibodies (mAbs), only cetuximab and panitumumab have been approved for the treatment of patients with metastatic colorectal cancer (mCRC) with RAS wild-type status [4–8].…”

“…To date, of the anti-EGFR monoclonal antibodies (mAbs), only cetuximab and panitumumab have been approved for the treatment of patients with metastatic colorectal cancer (mCRC) with RAS wild-type status [4–8]. However, no clear association has been found between the expression level of the EGFR protein in the tumours, determined by the FDA approved EGFR PharmDx™ kit, or other standard anti-EGFR antibodies, and the response to the EGFR inhibitors [3, 9–12]. We have previously shown that kits such as the EGFR PharmDx™, does not discriminate between the wtEGFR and EGFRvIII, and as such could have a major contribution to the lack of association between the expression of EGFR and response to anti-EGFR antibodies in such studies [13].…”

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

“…They exhibit aberrant signal transduction in many types of solid human cancers, including non-small cell lung cancer (NSCLC), breast cancer (BC), bladder cancer, ovarian cancer, colorectal cancer, pancreatic cancer and head and neck squamous cell cancer (HNSCC) (Ciardiello and Tortora 2008; Ioannou et al 2012; Khelwatty et al 2013). This exaggerated signalling may involve an enhanced signal input due to increased exposure to ErbB ligands (Modjtahedi and Dean 1994; Zhang et al 2007).…”