Cancer scientists at City St George’s, University of London have made a groundbreaking discovery of a new ‘molecular signature’, which drives drug resistance in an aggressive type of breast cancer known as HER2-positive breast cancer.

The study, being presented today at The Festival of Genomics and Biodata conference in London and published in the British Journal of Cancer, identified nine key red flags that appear to accelerate resistance to the drug lapatinib in HER2-positive breast cancer cells. Remarkably, seven of these had never been linked to HER2-positive breast cancer or lapatinib resistance before.

The results may explain why these patients develop resistance to the drug lapatinib – a targeted therapy used when other treatments fail. Lapatinib works by shutting down key processes inside cancer cells, slowing their growth and, in some cases, killing them altogether.

The team say that the results present a possible way forward for a new era of breast cancer treatments.

Dr Ateequllah Hayat, Lecturer in Drug Development from the School of Health & Medical Sciences at City St George’s, University of London, led the study. He 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 gain a detailed picture of how resistance to lapatinib develops, the researchers used a powerful combination of techniques to examine the molecular profile of HER2 breast cancer cells and lapatinib-resistance HER2 cells. They analysed the cells at multiple levels – examining how tightly or loosely the DNA was packaged by measuring the accessibility of DNA structures called chromatin, identified which genes were switched on or off, and determined which proteins were produced by the cells.

These three ‘molecular maps’ were layered on top of each other to determine the most consistent changes, and therefore those most likely to be true drivers of drug resistance.

The team discovered that lapatinib-resistant HER2 cancer cells exhibit a paradoxical behaviour. While their DNA was more tightly packaged overall with a reduction in chromatin accessibility compared to normal HER2 cancer cells, specific regions of DNA near key genes responsible for drug resistance to lapatinib were more open and active.

A total of nine genetic markers were consistently altered in breast cancer resistance. Seven new markers, HPGD, FASN, TPM1, CALD1, PCP4, AKR7A3 and KRT81, were discovered to be linked to breast cancer or lapatinib resistance for the first time, and EGFR and SCIN were already known to be involved resistance. These regions were linked to increased stress responses, actin remodelling and metabolic reprogramming, all of which could help cancer cells adapt to treatment.

The lapatinib-resistance HER2 cells were also found to be more irregular and less spherical in shape compared to normal HER2 cells, with protrusions that could help aggressively invade healthy cells.

The researchers then looked at lung cancer cells and found that two of the genes associated with resistance mechanisms – FASN and HPGD – were also increased with lapatinib resistance.

Dr 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.”

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