They found out why many non-smokers with lung cancer respond worse to therapy.

The study, published in the journal Nature Communications, shows that lung cancer cells with two specific genetic mutations are more likely to duplicate their genome, which helps them resist and develop resistance to treatment.

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers and is the most common type among nonsmokers.

In fact, lung cancer in people who have “never smoked” is the fifth leading cause of cancer death worldwide. The most common mutation in NSCLC is in the epidermal growth factor receptor (EGFR) gene, present in approximately 10–15% of cases and more common in nonsmokers. Survival rates for stage IV NSCLC and EGFR-mutated NSCLC are poor, with only one third of patients surviving up to three years.

EGFR inhibitors, available for more than 15 years, have shown mixed results. While some patients respond well, others, especially those with an additional mutation in the p53 gene, show no improvement and have worse survival rates.

To understand this discrepancy, the researchers reexamined data from a study of the latest EGFR inhibitor, Osimertinib. They found that while tumors with only the EGFR mutation shrank, tumors with both mutations had a “mixed response,” with some tumors growing, indicating rapid resistance to treatment.

Studies in mouse models with EGFR and p53 mutations have shown that resistant tumors have a high proportion of cells with duplicated genomes, giving them an advantage in drug resistance. Additional laboratory experiments confirmed that cells with a double mutation and a duplicated genome developed resistance in just five weeks.

“We showed that the combination of EGFR and p53 mutations, allowing for genome duplication, is associated with worse survival in patients with non-smoking-related lung cancer. “This increases the risk of developing drug-resistant cells due to chromosomal instability,” says Charles Swanton from the UCL Cancer Institute and the Francis Crick Institute.

Currently, patients with NSCLC are screened for EGFR and p53 mutations, but there is no standard test to detect whole-genome duplications. Researchers are already working to develop a diagnostic test for clinical use.

“Once we can identify patients with EGFR and p53 mutations whose tumors have whole genome duplications, we will be able to treat them more selectively,” explains Crispin Healy from the UCL Cancer Institute and consultant clinical oncologist at UCLH.

This discovery opens up the possibility of more personalized and effective treatment for patients with NSCLC, especially for those who have never smoked, potentially improving their survival and quality of life.