New Biomarker Signatures Reveal Lapatinib Resistance in HER2+ Breast Cancer: Ateequllah Hayat, PhD

Cancer scientists from City St George’s, University of London, identified 9 signatures associated with lapatinib resistance in patients with HER2-positive breast cancer.¹

The researchers presented their study findings at the Festival of Genomics and Biodata conference in London in late January 2026, addressing the high rate of relapse in breast cancer patients due to drug resistance. Nearly 70% of patients with breast cancer relapse after 5 years of treatment. However, these new findings have the potential to reshape clinical approaches to targeting aggressive HER2-positive tumor cells. The corresponding author of the study, Ateequllah Hayat, PhD, a lecturer in drug development at City St George’s, University of London, further discussed the study findings in an interview with The American Journal of Managed Care^®.

“If we validate this signature in other cancer models and in patient samples and really get to grips with the fact that this is truly involved in drug resistance, we could develop liquid biopsy-based assets,” Hayat said. “Detecting these changes in expression or epigenetically linked signatures from circulating tumor DNA or RNA could signal emerging resistance before clinical progression.”

Lapatinib is a dual kinase inhibitor that targets HER2 and epidermal growth factor receptor cells. It is frequently used in combination therapies to treat high-risk metastatic breast cancer patients and as a first-line therapy for treating HER2-positive breast cancer. However, numerous instances have indicated developed drug resistance in patients despite its initial efficacy.¹

In his study, Hayat and his team discovered 7 markers in drug resistance signatures that had not been implicated in HER2-positive breast cancer before, and 2 that had already been linked to drug resistance.¹ Yet, all 9 genetic markers were found to increase stress responses, actin remodeling, and metabolic reprogramming, all of which contribute to drug resistance.²

To distinguish the difference between cancer cells and lapatinib-resistant cells, Hayat and his team performed RNA sequencing and found a significant difference in gene expression patterns between the two cells.

“What we found was quite interesting. In this model, the opening up of the DNA chromatin is associated with oncogenic activation, but rather than the classical opening up associated with oncogenic activation, we instead saw that lapatinib-resistant cells displayed globally reduced chromatin accessibility,” Hayat explained. “That means that the DNA within these lapatinib-resistant cells actually became more compacted.”

The RNA sequencing revealed at least 17 differentially expressed histone-modifying enzymes, all of which play a key role in epigenetic regulation. This evidence suggests that lapatinib was not only forcing cancer cells to develop resistance but also mutating their DNA to evade the effects of the therapy overall.²

The next step is to validate these findings in other cancer models and patients to affirm that the identified genetic signatures are, in fact, involved in stimulating drug resistance, Hayat said.

“We expect significant hurdles because, again, this is a discovery stage, and there are quite a few stages left to actually get to that,” he said. “We would have to have diagnostic tools developed… Then we would want to do a clinical validation, which would be to integrate signatures into prospective trials to demonstrate improved outcomes and cost benefits.”

The diagnostic tools that would still need to be developed to help scientists easily detect and identify patients’ risk for drug resistance may include liquid biopsies or tissue-based panels, Hayat explained.

In the study, Hayat and his team analyzed the cells using 3 ‘molecular maps’ layered on top of one another to detect changes. They examined how densely the DNA was packaged, identified which genes were switched on or off, and determined which proteins the cells produced. Compounding these methods into a biological system can potentially help physicians prevent drug resistance in early therapy.

“We have developed a biological system to understand drug resistance, and we were also able to validate and confirm some of these biomarkers in a completely different system,” Hayat said. “Rather than waiting for these patients to become resistant, clinicians could potentially stratify patients based on the molecular signature or molecular risk and adjust the therapy proactively.”

References:

1. Breakthrough reveals hidden drivers of drug resistance in aggressive breast cancer. City St George’s University of London. January 2026. Accessed February 4, 2026. https://www.citystgeorges.ac.uk/news-and-events/news/2026/january/breakthrough-reveals-hidden-drivers-of-drug-resistance-in-aggressive-breast-cancer

2. Steggall J, Rajeeve V, Al-Subaie N, et al. Integrative proteo-genomic profiling uncovers key biomarkers of lapatinib resistance in HER2-positive breast cancer. BR J Cancer. 2025;133:1471-1482. doi:10.1038/s41416-025-03174-3