HER2 Targeted Therapy

HER2 Targeted Therapy: Introduction

HER2 belongs to a family of receptor tyrosine kinases (RTKs) that includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The gene for HER2 is located on chromosome 17 and has been found to be amplified with an increased copy number in several cancers. Amplification of HER2 has been found to promote tumorigenesis and to be involved in the pathogenesis of several human cancers.
To date, no ligand has been identified for HER2. However, HER2 appears to be the preferential dimerization partner for all members of the ERBB family. The binding of ligand followed by HER2 hetero-dimerization results in activation of HER2 tyrosine kinase activity. Activated HER2 then phosphorylates its substrates, leading to activation of multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation.

Amplification of the HER2 gene and/or overexpression at the messenger RNA or protein level occurs in about 20% of patients with early stage breast cancer. Before the advent of HER2-directed therapies, this increased level of HER2 was associated with high recurrence rates and increased mortality in patients. The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing now.

Although chemotherapy has shown to be an efficient strategy for adjuvant therapy in colorectal cancer, it is still not capable of preventing recurrence in all patients. Therefore there is numerous ongoing research for alternative compounds to be used as adjuvant therapy. Monoclonal antibodies and other biologicals, targeting tumor-associated proteins and blocking essential processes of the tumor, are extensively studied. A crucial step in this process is the identification of tumor specific proteins that can be targeted by these compounds. One of these targets is HER2, which is primarily associated with breast cancer.

Because symptoms are usually absent, 70 to 80% of patients with ovarian cancer will have advanced disease at the time of diagnosis. Despite an initial good response to first-line combination chemotherapy (taxane/platinum), relapses are frequent because of acquired chemoresistance. The use of new targeted therapies that are potentially effective in a subset of patients may be of great value.