Why many non-smokers develop deadly lung cancer

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Researchers from UCL, the Francis Crick Institute, and AstraZeneca have discovered why targeted treatments for non-small cell lung cancer (NSCLC) sometimes fail, particularly in patients who have never smoked.

Their study, published in Nature Communications, reveals that lung cancer cells with specific genetic mutations are more likely to double their genome, making them resistant to treatment.

Lung cancer is the third most common cancer in the UK and the leading cause of cancer death.

About 85% of lung cancer patients have NSCLC, the most common type in non-smokers. “Never smoked” lung cancer is the fifth most common cause of cancer death worldwide.

The most frequent genetic mutation in NSCLC involves the epidermal growth factor receptor gene (EGFR), found in 10–15% of NSCLC cases in the UK, especially among non-smokers. EGFR mutations enable cancer cells to grow faster.

While treatments targeting EGFR, known as EGFR inhibitors, have been available for over 15 years, their effectiveness varies.

Some patients see tumor shrinkage, but others, particularly those with an additional mutation in the p53 gene, do not respond well and have poorer survival rates. Until now, the reasons for this variability were unclear.

To uncover the cause, researchers re-analyzed data from trials of the latest EGFR inhibitor, osimertinib. They examined baseline and follow-up scans for patients with either only the EGFR mutation or both the EGFR and p53 mutations.

The team compared all tumors in the scans and found that patients with just the EGFR mutation showed tumor shrinkage. However, in patients with both mutations, some tumors grew, indicating rapid drug resistance. This “mixed response” is a challenge for oncologists.

Further investigation using a mouse model with both mutations revealed that resistant tumors had a higher number of cancer cells with doubled genomes, providing them extra copies of chromosomes. This genomic doubling makes the cells more resistant to treatment.

The researchers also treated lung cancer cells in the lab with an EGFR inhibitor. They observed that within five weeks, a significantly higher percentage of cells with both the double mutation and doubled genomes had developed into new drug-resistant cells.

Professor Charles Swanton from UCL Cancer Institute and the Francis Crick Institute explained that the combination of EGFR and p53 mutations causes genome doubling, increasing chromosomal instability and the likelihood of drug-resistant cells developing.

Currently, NSCLC patients are tested for EGFR and p53 mutations, but there is no standard test to detect whole genome doubling. The researchers are working on developing a diagnostic test for clinical use.

Dr. Crispin Hiley from UCL Cancer Institute and a Consultant Clinical Oncologist at UCLH noted that identifying patients with both mutations and genome doubling could lead to more personalized treatment.

This could involve intensive follow-up, early radiotherapy or ablation to target resistant tumors, or combining EGFR inhibitors with other drugs, including chemotherapy.

This study provides crucial insights into why some NSCLC patients, particularly non-smokers, develop resistance to targeted treatments, paving the way for more effective therapies.

If you care about lung health, please read studies about marijuana’s effects on lung health, and why some non-smokers get lung disease and some heavy smokers do not.

For more information about health, please see recent studies that olive oil may help you live longer, and vitamin D could help lower the risk of autoimmune diseases.

The research findings can be found in Nature Communications.

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