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

S. A. Mahmudova; F. R. Gudratova; B. G. Astanova; A. A. Aliyeva; A. Ch. Aliyeva; K. G. Gasimov

doi:10.7124/FEEO.v36.1724

S. A. Mahmudova Institute of Biophysics of the Ministry of Science and Education of the Republic of Azerbaijan, Baku, Azerbaijan https://orcid.org/0000-0001-8207-0544
F. R. Gudratova Institute of Biophysics of the Ministry of Science and Education of the Republic of Azerbaijan, Baku, Azerbaijan https://orcid.org/0009-0005-9597-5066
B. G. Astanova Institute of Biophysics of the Ministry of Science and Education of the Republic of Azerbaijan, Baku, Azerbaijan; Baku State University, Baku, Azerbaijan https://orcid.org/0000-0002-1379-5944
A. A. Aliyeva Institute of Biophysics of the Ministry of Science and Education of the Republic of Azerbaijan, Baku, Azerbaijan https://orcid.org/0009-0005-2826-0335
A. Ch. Aliyeva Institute of Biophysics of the Ministry of Science and Education of the Republic of Azerbaijan, Baku, Azerbaijan https://orcid.org/0009-0006-7504-2688
K. G. Gasimov Institute of Biophysics of the Ministry of Science and Education of the Republic of Azerbaijan, Baku, Azerbaijan https://orcid.org/0009-0009-2306-0114

DOI: https://doi.org/10.7124/FEEO.v36.1724

PDF

Keywords: ErbB receptors, heterodimerization, breast cancer, targeted therapy, humanized antybodies

Abstract

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.

References

Wee P., Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel). 2007. Vol. 9 (5). P. 52. https://doi.org/10.3390/cancers9050052.

Jiang N., Lin J. J., Wang J. et al. Novel treatment strategies for patients with HER2-positive breast cancer who do not benefit from current targeted therapy drugs. Exp. Ther. Med. 2018. Vol. 16 (3). P. 2183–2192. https://doi.org/10.3892/etm.2018.6459.

Larionov A. A. Current therapies for human epidermal growth factor receptor 2-positive metastatic breast cancer patients. Front. Oncol. 2018. Vol. 8. P. 89. https://doi.org/10.3389/fonc.2018.00089.

Tarantino P., Morganti S., Curigliano G. Targeting HER2 in breast cancer: new drugs and paradigms on the horizon. Explor Target Antitumor Ther. 2021. Vol. 2 (2). P. 139–155. https://doi.org/10.37349/etat.2021.00037.

Nami B., Maadi H., Wang Z. Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers (Basel). 2018. Vol. 10 (10). P. 342. https://doi.org/10.3390/cancers10100342.

Menendez J. A., Lupu R. Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited. Breast Cancer Res. 2007. Vol. 9 P. 111. https://doi.org/10.1186/bcr1773.

Yip H. Y. K., Papa A. Signaling pathways in cancer: therapeutic targets, combinatorial treatments, and new developments. Cells. 2021. Vol. 10 (3). P. 659. https://doi.org/10.3390/cells10030659.

Wolff A. C., Hammond M. E. H., Hicks D. G. et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology / College of American Pathologists clinical practice guideline update. Journal of Clinical Oncology. 2013. Vol. 31 (31). P. 3997–4013. https://doi.org/10.1200/JCO.2013.50.9984.

Cameron D., Piccart-Gebhart M. J., Gelber R. D. et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017. Vol. 389 (10075). P. 1195–1205. https://doi.org/10.1016/s0140-6736(16)32616-2.

Sendur M. A., Aksoy S., Altundag K. Pertuzumab in HER2-positive breast cancer. Curr. Med. Res. Opin. 2012. Vol. 28 (10). P. 1709–1716. https://doi.org/10.1185/03007995.2012.728132.

Maadi H., Soheilifar M. H., Choi W. S., Moshtaghian A., Wang Z. Trastuzumab mechanism of action; 20 Years of research to unravel a dilemma. Cancers (Basel). 2021. Vol. 13 (14). P. 3540. https://doi.org/10.3390/cancers13143540.

Derakhshani A., Rezaei Z., Safarpour H. et al. Overcoming trastuzumab resistance in HER2-positive breast cancer using combination therapy. J. Cell Physiol. 2020. Vol. 235 (4). P. 3142–3156. https://doi.org/10.1002/jcp.29216.

Mercogliano M. F., Bruni S., Mauro F. L., Schillaci R. Emerging targeted therapies for HER2-positive breast cancer. Cancers (Basel). 2023. Vol. 15 (7). P. 1987. https://doi.org/10.3390/cancers15071987.