COMPUTATIONAL ANALYSIS OF HER2 (ERBB2) AND ITS POTENTIAL AS A DRUG TARGET IN BREAST CANCER

Abstract

Background: HER2, is a receptor tyrosine kinase that is amplified or overexpressed in approximately 15–20% of breast cancers and drives aggressive tumor growth through PI3K/AKT/mTOR and RAS/MAPK signaling. Although HER2-targeted therapies have improved outcomes, variable treatment response, receptor heterogeneity, and resistance—particularly in kinase-domain and exon-20 insertion mutants—remain major clinical challenges.

Objective(s):To computationally evaluate the structural and functional characteristics of HER2 .

Methodology: A systematic computational analysis was performed using publicly available genomic, structural, and chemical databases. Machine-learning models were reviewed for inference of HER2 activity and prediction of inhibitor potency. Wild-type HER2 kinase-domain structures (PDB 3RCD and 3PP0) and the YVMA exon-20 insertion mutant structure (PDB 8U8X) were used for molecular docking of TAK-285, SYR127063, and Compound 27. Docking was performed using HADDOCK 2.4. Pathogenic mutations, including L755S, V777L, L869R, YVMA, and GSP insertions, were evaluated using SIFT, PolyPhen-2.

Results: SYR127063 showed the strongest predicted binding to wild-type HER2, with a docking score of −11.6 kcal/mol and MM-GBSA ΔG of −55.2 kcal/mol. Compound 27 exhibited preferential binding to the YVMA mutant, with a docking score of −11.6 kcal/mol and MM-GBSA ΔG of −52.6 kcal/mol. All ligand–receptor complexes remained stable during simulation, with RMSD values below 2.7 Å. Computational mutation analysis classified all evaluated HER2 mutations as damaging and predicted reduced sensitivity of exon-20 insertion mutants to TAK-285 and SYR127063.

Conclusion(s): Computational analysis supports HER2 as a rational and therapeutically actionable target in breast cancer. Integration of activity inference, structural modeling, mutation analysis, and drug repurposing may refine patient stratification, anticipate resistance mechanisms, and prioritize novel HER2-directed therapies. Experimental and clinical validation remains necessary before translational application.