Genetic Discovery Explains Drug Resistance in Breast Cancer

Researchers at City St George’s, University of London, have identified a new "molecular signature" that explains why some aggressive breast cancers become resistant to treatment. The study, published in the British Journal of Cancer, focused on HER2-positive breast cancer, a subtype that often develops resistance to targeted therapies such as Tykerb (lapatinib).

By layering multiple advanced genetic mapping techniques, scientists uncovered nine "red flags" or genetic markers that drive this resistance. Seven of these markers — including genes related to cell stress and metabolism — had never been linked to HER2-positive breast cancer before. The team discovered that even when treatment appears to be working, resistant cancer cells physically reshape themselves and activate specific "hidden" genetic pathways to survive and invade healthy tissue.

This discovery is a step toward more personalized medicine. CURE sat down for an interview with Dr. Ateequllah Hayat from the School of Health and Medical Sciences, who led the study, to discuss these findings and their significance for patients.

CURE: Your study found what's been described as invisible changes in cancer cells that lead to drug resistance. For a patient currently undergoing treatment, how would you describe these red flags and why were they so hard to find until now?

Hayat: That's a very good question. As a lab, what we're interested in is to understand how drug resistance takes place in a subtype of cancer called HER2-positive breast cancer. And so what we did, essentially, we mimic what happens in the clinic. So we took some breast cancer cells and made them resistant to a targeted therapy called [Tykerb]. Once we were able to establish this biological system, we then had the opportunity to use some of the state of the art techniques to really get a good and very in-depth resolution information on those cells. It was essentially reading those cells like a book, letter by letter.

And the kind of changes we focused on are called epigenetic changes, which are changes that have nothing to do with the DNA sequence itself. So it's not mutations, it doesn't change the genetic code. And what we find in those kind of studies, generally speaking, is that we get this canonical activation of oncogenes, so you get DNA opening, generally speaking, with more aggressive cells. But to our surprise, we found that these aggressive cells that were made resistant to [Tykerb] to this targeted therapy, the DNA was actually closing. It was becoming even tighter. But once we had a more in-depth look, we found in approximately nine key regions, there were nine key regulators that were actually opening. The DNA was opening around those particular regions, which was a very interesting finding for us. So there was something we call DNA landscape rewiring. So rather than this classical opening up, we found that those cells actually had reduced DNA accessibility with near-specific genes that drive resistance.

The other thing we found is something called the epigenetic modulator shifts. So we found this differential expression of these epigenetic enzymes called H tags, which highlight that there's a broad epigenetic regulators that are altered during resistance acquisition.

Tykerb is often a next step treatment when other therapies fail. How do these specific genetic markers change our understanding of why some patients stop responding to this drug, and does this discovery offer hope for keeping the treatment effective longer?

Again, that's a very good question. So, generally speaking, these HER2-positive breast cancer patients receive a combination of therapy: [Tykerb], which binds to what we call the intracellular tyrosine kinase domain of this HER2 protein receptor but in addition to that, some patients are also given, particularly in metastatic setting, when cancer spreads to other parts of the body, something called [Herceptin (trastuzumab)], which binds to the other side of the HER2 receptor called the extracellular binding domain.

Why this is very interesting is that what our study has shown is that it can actually contribute to this predictive value. What we are hoping to do now is to see if we can validate some of our findings, some of these biomarkers that we have identified in these cells, in other cancer models, in other cancer settings. If we are able to do that, we can then validate this in patient samples, so we can actually take patients who have become resistant to the same drug or similar drugs, and see if we can find this nine-marker signature, or nine biomarkers that we have found in our research so far. So this signature could identify patients who are intrinsically prone to develop resistance early in therapy, rather than waiting for clinical progression. So clinicians or doctors in the hospital could stratify patients based on molecular risk and adjust therapy proactively.

The other thing we could do is something called therapeutic stratification, so detection of high expression or these epigenetic changes that we have found, there's an argument that we could give these patients an alternative or combination therapy upfront. For example, we already said that we could give them these anti-HER2 therapies called [Tykerb], but also an epigenetic sensitizer, maybe a drug that is responsible for this epigenetic regulation of chromatin being open and closed.

The final and third thing would be the transition to something we call precision oncology. So generally speaking, the HER2-positive breast cancer patients undergo testing called the immunohistochemistry analysis, where we look at the HER2 protein overexpression in patients, or the FISH analysis, where you look at the gene expression patterns of the HER2, but essentially what that does is that it captures the protein overexpression or amplification, but it does not capture the dynamic resistance program of these key regulated genes, so a molecular signature that is sensitive to chromatin and expression changes could bridge this gap and inform more adaptive treatment strategies.

The study found that some of these markers, like FASN and HPGD, also appeared in lung cancer cells. Does this mean this discovery could eventually help patients with other types of aggressive cancers, and how close are we to seeing this applied across the board?

Yes, so this is exactly what we wanted to do, is actually to see if some of those proteins you mentioned, like HPGD or FASN, could be seen in some of the other cancer types. And so far, we have been able to test a few of those biomarkers, and you name some of them, which is HPGD and FASN, and we saw the same trend that we have seen in breast cancer to also be repeated in a subtype of lung cancer, which was very, very interesting for us, because it means that it does not matter what type of cancer we're looking at, [Tykerb]-acquired drug resistance might be taking the same route to acquire drug resistance across cancer types. And FASN is a very interesting one. It was consistently upregulated in the three different techniques that we use to screen those cancer cells, and it has some pharmacological inhibitors in development, which positions it as a druggable metabolic vulnerability. So a FASN is involved in metabolism, and it could be a key player. But we want to test some of the other biomarkers, not just in lung cancer, but we're interested in other cancers, like esophageal, endometrial, some hematological malignancies as well. And we look forward to seeing what happens, including afterwards, hopefully looking at patient samples as well.

For someone who's reading this, who may be feeling anxious about their own treatment's longevity, what's the most important takeaway message about how this research changes the outlook for their recovery?

The vast majority of patients, the current targeted therapies for breast cancer are excellent. They're targeted to a particular perturbations, particular aberration within the patient's DNA, and they work really well for a good amount of time. But unfortunately, there are mechanisms of resistance to those targeted therapies, and in particularly in the case of [Tykerb] or [Herceptin], and as I said in the beginning, which binds to the her two receptors and prevents signaling downstream, what we get in these resistant cells is that when cancer cells become resistant, they activate compensatory pathways. So instead of sending signaling through one protein, they just move to the neighboring protein and transmit the same signals. This is one of the mechanisms by which these cells become resistant. But the idea is, and this is where the initial idea of understanding these drug-resistant cells came to us, is to actually identify now new biomarkers that we can target so that these patients have more options that they can choose from, and that hopefully will have fewer toxicities and be more effective. That was the whole reasoning behind actually, this whole project.

References

1. “Breakthrough reveals hidden drivers of drug resistance in aggressive breast cancer,” news release; https://www.citystgeorges.ac.uk/news-and-events/news/2026/january/breakthrough-reveals-hidden-drivers-of-drug-resistance-in-aggressive-breast-cancer

Transcript has been edited for clarity and conciseness.

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