Structural organization of HER2-HER3 heterodimers and an approach to the therapy of breast and lung cancers

Breast cancer remains one of the most common carcinomas worldwide and is the leading cause of cancer-related death in women. A subset of these tumors – approximately 15% to 20% –are characterized by overexpression of HER2 receptor. Humanized monoclonal antibodies as therapeutic agents have significantly improved clinical outcomes targeting HER2. However, in many cases, the presence of multiple mutations such as substitutions, deletions, and insertions makes HER2 undetectable to these agents, even in HER2-HER3 complexes. Aim. In this study, we explore alternative sites on the ECD region of the HER2 and HER3 receptor proteins that may be potential epitopes for humanized monoclonal antibodies to treat these HER2-HER3-positive cancers. Methods. Analyses were performed on HER2 and HER3 sequences collected from the AlphaFold DB, EMBL-EBI UniProt, and NCBI PBD databases using NCBI BLAST, Print and ScanProsite, and PyMOL tools. Results. Comparative alignment of HER2 proteins revealed multiple deletion and/or insertion mutations where therapeutic agents bind the receptor protein. Further searching and analysis of the ECD region of both receptors revealed conserved residues and motifs on HER2 outside the pertuzumab and trastuzumab binding sites, as well as in the cysteine-rich region of HER3. Conclusions. Exploring and Understanding of these conserved residue organizations of HER2 and HER3 as a motifs may be used as alternative sites for the development of future therapeutic agents.