A gene signature associated with lapatinib resistance in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has revealed crucial molecular mechanisms that could guide future targeted therapies.
Despite advances in targeted treatments, over 70% of patients with HER2-positive breast cancer become refractory to treatment and relapse within five years, highlighting the urgent need to uncover biomarkers driving resistance.
The study, published in the British Journal of Cancer, used an integrative multiomics approach to develop a lapatinib-resistant breast cancer model from HER2-positive SKBR3 cells. The molecular changes underlying resistance were characterised through combined chromatin accessibility, transcriptomic and proteomic analyses.
Integration of these datasets identified a nine-marker resistance signature: SCIN, EGFR, HPGD, TPM1, CALD1, PCP4, AKR7A3, KRT81 and FASN. Notably, seven of these markers had not previously been linked to HER2-positive breast cancer.
Lapatinib resistance and chromatin accessibility
Lapatinib-resistant cells exhibited reduced overall chromatin accessibility and gene expression but showed increased accessibility and transcriptional activation at the loci of the identified biomarkers. Functionally, these cells demonstrated enhanced anchorage-independent growth and invasiveness.
Pathway analysis revealed alterations in actin cytoskeleton organisation, KRAS and MAPK signalling, and double-strand DNA repair, all of which are associated with tumour aggressiveness and chemoresistance.
Proteomic analysis confirmed elevated expression of several markers, including HPGD andFASN, which were validated in an independent lapatinib-resistant lung cancer model, suggesting that the signature may reflect a broader mechanism of resistance across tumour types.
The researchers noted that in vitro models may not fully replicate the tumour microenvironment, emphasising the need for further validation in physiologically relevant systems.
Overall, the multiomics approach demonstrated how chromatin remodelling drives changes in gene expression and protein levels, linking genetic and epigenetic factors in cancer progression.
The researchers noted that this gene signature could extend to other cancer types and provide a framework for future studies, with potential as a biomarker or therapeutic target to overcome acquired drug resistance.
Reference
Stegall J et al. Integrative proteo-genomic profiling uncovers key biomarkers of lapatinib resistance in HER2-positive breast cancer. Br J Cancer 2025;133:1471–82.
