Fast-tracked cancer drug candidate causes substantial levels of mutations and must be investigated for risk of secondary cancer

1 Dec 2023
Fast-tracked cancer drug candidate causes substantial levels of mutations and must be investigated for risk of secondary cancer

A cancer drug fast-tracked into clinical trials in the United States could be more damaging to DNA than tobacco smoke, warn Cambridge researchers.

The drug, known as CX-5461 or pidnarulex, is one of a class of drugs that are meant to induce ‘synthetic lethality’ targeted specifically at tumour cells while leaving non-cancerous cells untouched.

But in a study published today in Nature Genetics, a team from the Early Cancer Institute at the University of Cambridge shows that the drug causes a significant number of mutations to the DNA of all cells, regardless of whether tumour or normal cells, potentially increasing a patient’s risk of secondary cancers if they were exposed to this drug.

The drug is not available to patients in the UK and no clinical trials of the drug for cancer treatment are currently open in the UK.

Professor Serena Nik-Zainal, a National Institute for Health and Care Research (NIHR) Professor who led the research, said: “Drugs that operate on the principle of synthetic lethality are meant to be targeted only at cancer cells. There are several already in use – such as PARP inhibitors – that we know are safe and effective. Pidnarulex does target cancer cells but we were surprised to see how damaging it is to non-cancerous cells – a discovery we made entirely by chance.”

Professor Nik-Zainal’s team has shown previously that the DNA inside our cells can be damaged by environmental factors, causing mutations that accumulate over time as cells divide and replicate, and can lead to the development of tumours.

Each environmental factor leaves its own characteristic ‘fingerprint’, allowing scientists to identify the likely cause of a tumour. Among the most dangerous common environmental factors are UV light and tobacco smoke. The DNA in a tumour cell of a lung cancer patient who has smoked most of their life will typically display several tens of thousands of mutations.

Drugs that induce so-called synthetic lethality are believed to only target tumour cells. PARP inhibitors, for example, only work on cells in which both copies of the BRCA1 or BRCA2 genes have stopped working – that is, tumour cells.

In 2022, it was announced that the US medicines regulator, the Food and Drug Administration (FDA), has fast-tracked pidnarulex into early-stage clinical trials for ovarian and breast cancer with mutations in certain genes, such as BRCA1, BRCA2 and PALB2. The trials involve small numbers of patients and the drug does not have approval from the FDA for wider prescription in the US.

When the Cambridge team analysed cells that had been treated with pidnarulex, they found that, as expected, it induced synthetic lethality in BRCA1- and BRCA2-deficient cells. But surprisingly, it also caused extensive mutations in the DNA of all cells, and at magnitudes that exceed known environmental carcinogens such as smoking, raising the risk that it would promote secondary cancers.

Although it is impossible to say whether individual mutations increase the risk of cancer, it is the likely overall burden that is important.

“All we did was treat the cells with the drug for two hours and already we could see mutations in individual cells. Patients are likely to be receiving longer exposures to this compound,” said Dr Gene Koh, Senior Research Associate and first author of the publication.

Professor Nik-Zainal said the discovery could not necessarily have been foreseen, as the idea of looking for mutagenesis – the characteristic fingerprints left behind by environmental damage – is still relatively new.

“It was unusual that a synthetic lethality drug should have such an effect,” she said. “I don’t think anyone would have expected to see this. We hope this information will be treated with urgency by those currently running clinical trials of the drugs.”

The team has alerted the pharmaceutical company that manufactures the drugs, and also conveyed their findings to relevant clinicians leading their clinical trials.

The research was mainly funded by Cancer Research UK, with support from the NIHR Cambridge Biomedical Research Centre.

Director of Evidence and Implementation at Cancer Research UK, Naser Turabi, said: “This research has uncovered potentially concerning information about pidnarulex, thanks to Professor Nik-Zainal’s use of cutting-edge techniques which can read cancer’s genetic code in full and identify mutations triggered by environmental factors.

“This drug is not currently available in the UK and there are no risks to patients here. No clinical trials are open in the UK for the drug and it doesn’t have the necessary approvals to be offered by any doctor here. Where it is available in clinical trials in the US and Australia, we hope regulators and the company who make pidnarulex will consider this evidence carefully in their ongoing evaluations of the drug.

“Clinical trials are designed to identify benefits and risks of new medicines, and play a key role in ensuring that patients get the best possible care. All clinical trials in the UK undergo rigorous safety assessments and research like this plays an important role in ensuring any new medicines for treating cancer are safe and effective.

Source: University of Cambridge