Drugs targeting HER2 have shown excellent clinical efficacy over the 20 years, achieving one milestone after another in the field of cancer therapeutics. This article mainly introduces the development history of HER2-targeted drugs and the latest clinical breakthrough: Trastuzumab.
Introduction to HER2 targets
There are four members in the HER receptor family. They are epidermal growth factor (EGF) receptors (EGFR/HER1/ErbB1, HER2/ErbB2, HER3/ErbB3, and HER4/ErbB4). HER2 has the strongest catalytic kinase activity and can function as the most active signaling complex after dimerization with other HER family members.
HER2 consists of three domains: an extracellular ligand-binding domain (ECD), a short transmembrane region, and an intracellular tyrosine kinase domain. The current strategies used to target HER2 include monoclonal antibodies (mAbs), small molecule tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), bispecific antibodies, and cell-based therapies (T cells and NK cells).
It is found that the frequent HER2 mutations are S310, L755, Y772_A775dup, and V777. Bladder cancer is dominated by extracellular domain mutations, breast cancer and colon cancer by kinase domain missense mutations, and lung cancer by kinase domain insertions. In non-small cell lung cancer (NSCLC), exon 20 insertion is the most common HER2 mutation (96%), and A775_G776insYVMA insertion is found in 83% of cases.
Mutations in exon 20 of HER2 also include point mutations, such as L755S and G776C (8% to 10%). Some less common mutations affecting transmembrane and parafembrane domains (G660D, R678Q, E693K, and Q709L) have recently been reported. HER2 mutations and other oncogenic factors, such as EGFR, KRAS, NRAS, ALK, PI3KCA, and BRAF, have previously been proven to be mutually exclusive.
At present, HER2 is detected in breast cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, lung cancer, and other cancer types. The detection rate of HER2 high expression is about 2.5% in lung cancer, 15%-25% in breast cancer, 20% in gastric cancer, 20% in cholangiocarcinoma, 27% in ovarian cancer, and 18%-80% in endometrial cancer. It can be forecast that the continuous development of drugs targeting HER2 has brought great hope to the treatment of cancer.
Development history of HER2-targeted drugs
Trastuzumab (Herceptin), the first HER2-targeted mAb on the market since 1998, has not only changed the treatment landscape for patients with HER2-positive breast cancer but also promoted clinical revolution. However, some patients may develop resistance or relapse. Lapatinib, a small-molecule TKI drug, was introduced in 2007. The approved indication is the combination of Capecitabine for HER2-positive patients with advanced or metastatic breast cancer and previously treated with Anthracyclines, Paclitaxel, and Trastuzumab. In 2013, the first ADC Kadcyla was launched, which, like an upgraded version of Trastuzumab, not only achieved desired treatment effects but also had fewer toxic reactions and was more tolerated by patients. Since then, HER2 drugs have occupied a place in the fields of monospecific antibodies, small molecular drugs, and ADCs. Targeted drugs have flourished in many areas, such as breast cancer, gastric cancer, and non-small cell lung cancer.
“Miracle drug” for breast cancer: Enhertu (DS-8201)–Trastuzumab
As for HER2-targeted drugs, we have to mention Enhertu, the blockbuster product at the 2022 ASCO meeting. It is a new-generation ADC drug that links the humanized monoclonal antibody Trastuzumab targeting HER2 to a novel topoisomerase 1 inhibitor exatecan derivative (DX-8951 derivative, DXd) through a 4-peptide linker. Targeted delivery of cytotoxins into cancer cells results in reduced systemic exposure of cytotoxic agents compared with general chemotherapy.
The advantages of Trastuzumab
(1) Safety
a. Fewer toxins: each Trastuzumab molecule is attached to eight Deruxtecan molecules, compared with 3.5 toxin molecules for Trastuzumab emtansine.
b. Stability: the 4-peptide linker selected by T-DXd is very stable in the peripheral circulation system, with almost no toxin released and a low incidence rate of off-target effects. Therefore, the toxicity is further controlled.
c. High membrane Permeability: its toxin, Dxd, penetrates cell membranes easily and produces a by-standard effect even before cell lysis.
(2) Efficacy
The efficacy of Trastuzumab Deruxtecan is not limited to HER2 positivity. Patients with low HER2 expression but negative gene expression also benefit from it.
Conclusion
The HER2-positive breast cancer therapeutics are rapidly evolving, thereby improving the prognosis and life quality of patients diagnosed with early-stage and metastatic disease. However, there are still many unsolved problems, and clinical trials are ongoing to further optimize the efficacy of therapies.
Related Products:
| Name | CAS | Description |
| EGFR Inhibitors | The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases. | |
| Topoisomerase Inhibitors | Topoisomerase enzyme inhibitors are a class of drugs acting directly on the cells. | |
| ADCs | Antibody-drug conjugates or ADCs consist of an antibody, a cytotoxic drug, and a linker that attaches the two. | |
| Paclitaxel | 33069-62-4 | Paclitaxel is a compound with anti-tumor activity extracted from the Pacific yew tree Taxus brevifolia. |
| Exatecan | 171335-80-1 | Exatecan is an inhibitor of DNA topoisomerase I, with an IC50 of 2.2 μM (0.975 μg/mL). It can be used to study cancer. |
| Deruxtecan | 1599440-13-7 | Deruxtecan, a topoisomerase I inhibitor, is an exatecan derivative (DX-8951 derivative) with a cleavable pepetide linker and a maleimide group. |
| Trastuzumab emtansine | 1018448-65-1 | Trastuzumab emtansine is an antibody-drug conjugate (ADC) with potential antitumor activity. |