HER2 as an Emerging Oncotarget for Colorectal Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy

Abstract

Amplification of the HER2 gene is an indicator of poor prognosis for several kinds of malignancies such as breast and gastric cancer, and anti-HER2 targeting therapies provide clinical benefits in these patients. In 2011, HER2 was identified as a resistance molecule for de novo and secondary anti-epidermal growth factor receptor (EGFR) antibody therapy. HER2 activation provides a bypass signaling pathway after anti-EGFR antibody treatment of colorectal cancer. Cell line-based screening revealed that HER2 genomic amplification induces resistance to the anti-EGFR antibody cetuximab in colorectal cancer. Recently, HER2 itself has been recognized as a target for oncotherapy in colorectal cancer. The first part of this review provides an update on the present state of knowledge about the role of HER2 in colorectal cancer, including its prognostic relevance and role in resistance to anti-EGFR antibody treatment. In the second part of the review, we discuss the results of preclinical and clinical studies that examined the potential utility of anti-HER2 targeted therapy in colorectal cancer. Although it acts as a barrier for other molecular targeting agents such as cetuximab, HER2 itself is a promising target for oncotherapy. Current research indicates that anti-HER2 drugs will be developed further and introduced into clinical practice for the treatment of patients with HER2-positive colorectal cancer.

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide. More than 1.2 million new cases of CRC are diagnosed every year.¹ Approximately 25% of these patients have metastatic lesions at diagnosis and almost 50% of these patients will eventually develop metastases.² The standard therapy for advanced CRC is systemic chemotherapy. Until the 2000s, 5-fluorouracil was the only drug approved by the US Food and Drug Administration (FDA) for the treatment of metastatic CRC; however, median overall survival after treatment was <1.5 years.³ Subsequently, the development and the US FDA approval of new agents such as irinotecan, oxaliplatin, and bevacizumab further improved patient survival.4, 5, 6 The anti-epidermal growth factor receptor (EGFR) antibody cetuximab was approved in the United States and Europe in 2004, and another anti-EGFR antibody panitumumab was approved in 2006. Anti-EGFR antibodies bind to the extracellular domain of the EGFR, and prevent its activation by EGFR ligands such as epidermal growth factor and amphiregulin. Consequently, they inhibit the subsequent downstream signaling mediated by the RAS-RAF-extracellular signal-related kinase (ERK) and phosphoinositide 3-kinase (PI3K)-phosphatase and tensin homolog (PTEN)-AKT pathways. Early clinical trials revealed significant but limited efficacy of anti-EGFR antibodies in patients with CRC because some of these patients had a primary resistance to these agents, and patients who initially responded to treatment inevitably became refractory to those agents.7, 8 However, these anti-EGFR antibodies improved overall survival in some patients with CRC, especially in those with wild type RAS.9, 10 Since then, several mechanisms for resistance to anti-EGFR antibody therapy have been discovered in CRC. For example, mutations in KRAS, NRAS, BRAF, and PIC3CA, and loss of PTEN results in resistance to anti-EGFR therapies.11, 12, 13, 14 Furthermore HER2 amplification was identified in anti-EGFR antibody-resistant CRC, and HER2 was identified as the mediator of the bypass signaling.¹⁵