Anti HER2 Targeted Therapy

Abstract: HER2 is the transmembrane glycoprotein of epidermal growth factor receptor family, involved in cell proliferation and differentiation. Abnormal expression or mutation is closely related to tumor invasiveness and poor prognosis. This article summarizes HER2 targeted therapy, biological characteristics, signaling pathway and regulatory mechanism.

Keywords: HER2 Targeted Therapy, HER2 Protein Function, HER2 Signaling Pathway

1. HER2 Structure

HER2 structure includes extracellular domain, transmembrane region and intracellular tyrosine kinase domain. Extracellular domain consists of four subdomains responsible for dimerization. Transmembrane region helps receptor localization. Intracellular kinase domain initiates signal transduction. HER2 doesn't have identified ligands. Dimer helps activation of downstream pathway and promotes cell proliferation. Involvements in development of various cancers are wide.

2. Regulation of Signaling Pathway and Function

HER2 signaling pathway plays an important role in cell growth, viability and differentiation. HER2 mainly activates signal transduction via heterodimer formed with other EGFR family members. In breast cancer, HER2 usually forms heterodimer with HER3. Obvious activation of PI3K/AKT and MAPK signaling pathway promotes cell proliferation and viability. Expression of HER2 in gastric cancer shows strong heterogeneity, possibly forming dimer with HER3 and other EGFR family members. The tumor invasiveness is also enhanced. The mutation(e.g. insertion of exon 20) of HER2 in non-small cell lung cancer(NSCLC) promotes the activated signal without ligands and tumor development. HER2 in rectal cancer can dimerize with EGFR, affecting curative effect of anti-EGFR drugs(e.g. Cetuximab). Besides, over-expression of HER2 and formation of dimer are found in some ovarian cancers, also involved in tumor progression. Forms of different dimers reflect complex roles of HER2 in various cancers.

3. Interaction between HER2 and EGFR Family Members

HER2 can form homodimer or heterodimer with EGFR family members. The activity of heterodimer signaling is stronger. HER2/HER1 dimer enhances oncogenic signals. HER3 lacks kinase activity but has phosphor-tyrosine sites. HER2/HER3 dimer strongly activates downstream pathway, commonly found in breast cancer and prostatic cancer. HER2 can also dimerize with HER4. Weaker effects are involved in mammary gland development and lactation.

4. Role of HER2 in Tumor Biology

Over-expression of HER2 is usually found in 20%-30% breast cancer. Promoted abnormal proliferation and invasion of cancer cells result in poor prognosis. HER2 targeted drugs(e.g. Trastuzumab, Neratinib etc) can effectively block signaling pathway and improve patients' prognosis. Abnormality of HER2 also appears in various cancers(e.g. gastric cancer, NSCLC). Drug resistance is the therapeutic difficulty.

5. HER2 based Therapy and Strategy

HER2 targeted drugs greatly improve HER2 positive tumor, especially for therapeutic effect of breast cancer. Trastuzumab is the first monoclonal antibody targeting HER2. Inhibition of HER2 dimerization and induction of antibody-dependent cytotoxicity obviously improve patients’ prognosis. Lapatinib and Neratinib are small molecule tyrosine kinase inhibitors, commonly blocking downstream signal combination therapy. Pertuzumab and Trastuzumab can improve anti-tumor activity. T-DM1 and T-DXd are antibody conjugated drugs with better therapeutic effect , accurately delivering cytotoxic drugs. Margetuximab is the optimized Fc antibody. Using with chemotherapy together for advanced patients promotes the development of HER2 targeted therapy.

Further researches about HER2 cover development of new targeted drugs, optimized treatments and exploration for drug resistance mechanism. Therapeutic effect and prognosis for HER2-positive patients are expected to be improved, with the contribution from artificial intelligence, machine learning based big data analysis, new drug delivery and clinical trials.

REFERENCES

[1]Spatial profiling of patient-matched HER2 positive gastric cancer reveals resistance mechanisms to targeted therapy, PMID: 41167802.
[2]Identification of new selective CD36 inhibitors to potentiate HER2-targeted therapy in HER2-positive breast cancer, PMID: 40770043.