Can HER3 Become a Therapeutic Target?

With the increasingly fierce competition in the field of oncology drug R&D, the exploration of various drug forms based on established drug targets is a relatively low-risk R&D option. However, the commercialized drug targets that have been successfully operated are already very competitive. Therefore, in order to avoid the foreseeable competition in the Red Ocean market as much as possible, choosing targets with similar functions should be a better choice for many pharmaceutical companies.

The popularity of HER2 (human epidermal growth factor receptor 2, also known as ERBB2 https://www.antibody-creativebiolabs.com/symbolsearch-erbb2.htm) is not lost to PD-1 as a drug target in tumor immunotherapy, and the reputation of anti-HER2 monoclonal antibody (mAb) trastuzumab is not lost. There are a lot of anti-PD-1 mAbs, and the development of ADC drugs against the HER2 target is also the current fierce competition.

It is worth mentioning that HER2 is a mature target for tumor therapy. So far, no ligand that can directly bind to HER2 has been found in the human body, which must form a homodimer or heterodimer with other members of the family (such as HER3). After the dimerization of HER2, the conformation changes, which stimulates the activity of intracellular tyrosine kinases, and then activates downstream pathway nodes (MAPK signaling pathway and PI3K/AKT signaling pathway), thereby exerting corresponding physiological effects.

In addition, HER3 is expressed in the gastrointestinal tract, reproductive system, skin, nervous system, urinary tract, and endocrine system of human, while the overexpression of HER3 protein is associated with many cancers, including prostate cancer, bladder cancer, and breast cancer.

Based on this, many R&D institutes have also shifted their attention from the highly competitive HER2 to HER3, hoping that this target in the same family as HER2 can also serve as a new target for tumor treatment.

The reason for the slow progress in the development of tumor drugs targeting HER3 is that HER3 itself has low binding capacity, does not have the intrinsic kinase activity of other family members such as HER2, and does not have a suitable biomarker that reflects whether HER3 is activated or not, causing great difficulties in drug development.

At present, the perfect match of HER3 is another star target—NRG 1 (ligand neuregulin 1, also known as HRG 1), a member of the epidermal growth factor (EGF) ligand family. In the body, NRG1 can bind to HER3 to change its conformation, thereby realizing dimerization, phosphorylation, and activation of signal pathways. It can be judged that HER2, HER3, and NRG are important upstream signal sources of signaling pathways such as PI3K/AKT and MAPK. Based on the bridging role of HER3, by targeting HER3, then blocking the formation of HER3/HER2 heterodimer or blocking the binding of NRG and HER3, will bring new breakthroughs in the treatment of cancer theoretically.

Particularly, NRG1 (https://www.antibody-creativebiolabs.com/symbolsearch-nrg1.htm) can be used as a HER3 target drug to activate biomarker, and NRG1 gene fusion occurs in 0.2% of solid tumors, including lung cancer, breast cancer, and ovarian cancer, and the incidence is high in certain subtypes, such as lung infiltration mucinous adenocarcinoma (7%-31%) and pancreatic ductal adenocarcinoma (6%).

In addition, due to the mutually exclusive mechanism of carcinogenesis, when NRG1 fusion proteins are found in tumors, there are usually no other known oncogenic driver gene mutations, such as EGFR, KRAS, ALK, ROS1, and RET mutations. Based on the above advantages, NRG1 itself is a perfect effective target for tumor treatment. Coupled with the current commonly used clinical chemotherapy and immunotherapy, the treatment response is not good for patients with NRG1 fusion. The R&D of HER3-related drugs is worth looking forward to for patients with NRG1 fusion tumors.