Researchers from UCL, the Francis Crick Institute, and AstraZeneca have discovered why targeted treatments for non-small cell lung cancer (NSCLC) often fail for patients who have never smoked. Their study, published in *Nature Communications*, reveals that lung cancer cells with two specific genetic mutations are more likely to double their genome, making them more resistant to treatment.
Prevalence and Impact of NSCLC Lung cancer is the third most common type of cancer in the UK and the leading cause of cancer death. Around 85% of lung cancer cases are NSCLC, which is also the most common type among non-smokers. “Never smoked” lung cancer is the fifth-most common cause of cancer death globally. The most common genetic mutation in NSCLC is in the epidermal growth factor receptor (EGFR) gene, which is found in about 10-15% of NSCLC cases in the UK, especially among non-smokers.
Challenges with EGFR Inhibitors For over 15 years, treatments targeting the EGFR mutation, known as EGFR inhibitors, have been available. However, patients with an additional mutation in the p53 gene often do not respond well to these treatments and have worse survival rates. The reason for this discrepancy has remained unclear until now.
Research Findings The researchers re-analyzed data from trials of the latest EGFR inhibitor, osimertinib. They compared baseline scans and follow-up scans of patients with either only the EGFR mutation or both the EGFR and p53 mutations. They found that while tumors in patients with only the EGFR mutation generally shrank, those with both mutations exhibited a “mixed response,” where some tumors shrank, and others grew, indicating rapid drug resistance.
Further investigation using a mouse model with both mutations showed that resistant tumors had a higher number of cancer cells that had doubled their genome, leading to extra copies of all their chromosomes. When treated with an EGFR inhibitor, cells with both mutations and doubled genomes developed drug resistance more quickly.
Implications for Treatment Professor Charles Swanton from UCL Cancer Institute and the Francis Crick Institute explained that the combination of EGFR and p53 mutations leads to genome doubling, which increases the risk of drug-resistant cells due to chromosomal instability. Although patients with NSCLC are tested for EGFR and p53 mutations, there is no standard test for detecting whole genome doubling. The researchers aim to develop a diagnostic test to identify this condition.
Dr. Crispin Hiley from UCL Cancer Institute and a Consultant Clinical Oncologist at UCLH emphasized that identifying patients with both mutations and genome doubling could lead to more selective treatments. This might involve more intensive follow-up, early radiotherapy or ablation, or early use of combinations of EGFR inhibitors with other drugs, including chemotherapy.
