Researchers at City St George’s, University of London have uncovered a novel “molecular signature” that drives resistance to lapatinib in HER2-positive breast cancer, offering new hope for personalized treatment strategies.
The study, presented at The Festival of Genomics and Biodata Conference in London and published in the British Journal of Cancer, identified nine key genetic markers that accelerate lapatinib resistance in aggressive HER2-positive breast cancer cells. Notably, seven of these markers—HPGD, FASN, TPM1, CALD1, PCP4, AKR7A3, and KRT81—had never previously been associated with HER2-positive breast cancer or resistance to lapatinib.
Lapatinib, a targeted therapy used when other treatments fail, works by disrupting critical processes in cancer cells to slow growth and, in some cases, induce cell death. However, resistance remains a major challenge, with over 70% of patients relapsing within five years of treatment.
Dr Ateequllah Hayat, Lecturer in Drug Development at City St George’s, University of London, led the research. He explained: “By combining several advanced techniques, we uncovered subtle but crucial changes in cancer cells that were previously invisible. These findings provide new insight into why some patients develop drug resistance and point toward potential strategies to prevent it.”
To map the mechanisms behind resistance, the team conducted a multi-level analysis of HER2-positive cancer cells. They examined chromatin accessibility to understand DNA packaging, analyzed gene expression patterns, and assessed protein production. Overlaying these “molecular maps” revealed consistent changes most likely driving lapatinib resistance.
Interestingly, lapatinib-resistant HER2 cells displayed paradoxical behavior: while their DNA was generally more tightly packed, regions near key drug-resistance genes were more open and active. The researchers also observed structural changes in resistant cells, including irregular shapes and protrusions that could enhance their ability to invade healthy tissue.
Beyond breast cancer, the study found that two resistance-related genes, FASN and HPGD, were also elevated in lung cancer cells exposed to lapatinib, suggesting the nine-gene signature may have broader relevance.
Dr Hayat emphasized the potential impact of the discovery: “This nine-marker resistance signature opens the door to biomarker-guided therapies that could prevent or reverse drug resistance. It represents a major step toward more personalized, effective cancer treatments, giving patients more options.”
The research offers hope for a future in which drug resistance is no longer an inevitable outcome but a predictable and manageable process, allowing clinicians to tailor treatments to each patient’s molecular profile.
