Scientists find how lung cancer mutations impact treatment response

Why are some lung cancers more difficult to treat than others? A team of researchers may have found a new clue. 

A recent study found that two specific genetic mutations influence cancerous cells and make them more likely to resist treatment.

The mutations concern the genes EGFR, which is involved in cell growth, and TP53, which helps regulate cell division and prevent tumours.

Mutations in these proteins are often hallmarks of cancer which is why the team of researchers from the University College London (UCL), the UK-based Francis Crick Institute and AstraZeneca investigated them using mouse and in vitro models. 

They published their findings in the journalNature Communications.

Non-small cell lung cancer (NSCLC) is one of the most common forms of lung cancer making up 80 to 85 per cent of them.

Mutations of the EGFR, which stands for epidermal growth factor receptor gene, are very common in this type of cancer enabling cancerous cells to grow faster. It is also often found in patients who have never smoked.

Treatments targeting this mutation, known as EGFR inhibitors, have been available for over 15 years with mixed results. Some patients saw their cancerous tumours shrink with the treatment while others had a poorer response.

When comparing patients’ scans treated with an EGFR inhibitor called osimertinib, researchers found that in patients with just the EGFR mutations, tumours reduced in size in response to the treatment.

However, in patients with both the EGFR and TP53 mutations, the results were more complex.

While some tumours had shrunk, others had grown, providing evidence of drug resistance. This phenomenon is called a “mixed response” and poses a challenge to treatment.

The researchers used a mouse model with both mutations and found that in drug-resistant tumours in mice, more cancer cells doubled their genome, resulting in extra copies of their chromosomes.

“We’ve shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer, which is the combination of EGFR and p53 mutations enabling genome doubling,” Charles Swanton, from UCL Cancer Institute and the Francis Crick Institute, said in a statement. 

“This increases the risk of drug-resistant cells developing through chromosomal instability,” he added. 

Paving the way for better care

Lung cancer is the fourth most frequent cancer and the leading cause of cancer-related deaths in the EU, accounting for over 20 per cent of them.

Only around a third of patients with stage four NSCLC and an EGFR mutation survive for up to three years.

While doctors test non-small cell lung cancer patients for EGFR and p53 mutations to guide treatment, there’s no current test widely used to detect whole genome doubling.

Researchers are developing a diagnostic tool to identify this specific mutation.

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“Once we can identify patients with both EGFR and p53 mutations whose tumours display whole genome doubling, we can then treat these patients in a more selective way,” said Dr Crispin Hiley, from the UCL Cancer Institute. 

“This might mean more intensive follow-up, early radiotherapy or ablation to target resistant tumours, or early use of combinations of EGFR inhibitors, such as osimertinib, with other drugs including chemotherapy,” he added.