Researchers at City St George’s, University of London have identified a molecular signature associated with resistance to lapatinib in HER2-positive breast cancer, with the findings presented at the Festival of Genomics and Biodata conference and published in the British Journal of Cancer.

The study identified nine genetic markers linked to resistance to the HER2-targeted therapy, including seven that had not previously been associated with HER2-positive breast cancer or lapatinib resistance. The researchers said the findings could help explain why patients often develop resistance to the drug and could inform biomarker-guided treatment strategies.

Lapatinib is used in HER2-positive breast cancer when other treatments fail, working by inhibiting signalling pathways that drive tumour growth. However, resistance frequently develops, limiting long-term effectiveness.

Ateequllah Hayat, lecturer in drug development at City St George’s, University of London, led the study and said: “Over 70% of breast cancer patients relapse within five years of treatment, and drug resistance remains one of the biggest challenges in cancer care. By combining several advanced techniques, we were able to uncover subtle but critical changes in the cancer cells that were previously invisible.”

To investigate resistance mechanisms, the researchers analysed HER2-positive breast cancer cells and lapatinib-resistant cells using a combination of chromatin accessibility profiling, gene expression analysis and protein profiling. The integrated approach allowed the team to identify consistent molecular changes associated with resistance.

The researchers found that resistant cancer cells showed reduced chromatin accessibility overall, but increased accessibility in specific regions near genes associated with resistance. Nine genetic markers were consistently altered, including HPGD, FASN, TPM1, CALD1, PCP4, AKR7A3 and KRT81, which were newly linked to HER2-positive breast cancer or lapatinib resistance, alongside EGFR and SCIN, which had been previously implicated.

These markers were associated with stress response pathways, actin remodelling and metabolic reprogramming, processes that could support tumour cell survival and adaptation to treatment. The resistant cells also showed altered morphology, with more irregular shapes and protrusions that could facilitate invasion of healthy tissue.

The researchers extended their analysis to lung cancer cells and reported that two of the resistance-associated genes, FASN and HPGD, were also increased in lapatinib-resistant lung cancer cells, suggesting the signature could be relevant beyond breast cancer.

Hayat added: “Our results suggest that our nine-marker resistance signature may be found in other types of cancer beyond breast cancer. This work opens the door to developing biomarker-guided therapies that could prevent or reverse drug resistance. It’s a major step toward more personalised and effective cancer treatments to give patients more options.”

He added: “Ultimately, the hope is that resistance will no longer be an inevitable outcome, but rather a predictable process that can be prevented.”

While the findings are based on laboratory models, they highlight potential targets for future biomarker-driven treatment strategies and provide insight into how resistance develops at the molecular level. The study represents early-stage research, and further validation in clinical samples will be required before the markers can be used in patient stratification or therapeutic development.

The announcement is positioned as a research advance rather than a commercial development, with no clinical development timelines or product plans disclosed.