Non-small cell lung cancer (NSCLC) accounts for more than 8 out of 10 malignant lung tumors. The survival rate varies depending on how advanced the disease is when it is diagnosed. One treatment for NSCLC involves targeting the EGFR mutation, which is known to be a risk factor. While it is effective on some patients, the drugs do not work on others, particularly those with an additional mutation in the p53 gene (which plays a role in suppressing tumors) and those who have never smoked.
Researchers from the Cancer Institute and the Francis Crick Institute at University College London wanted to understand the origin of these differences in prognosis with this type of lung cancer.
Lung cancer: EGFR and p53 mutations reduce survival
To study why some non-small cell lung cancers were resistant to treatment, the team repeated a study conducted on EGFR inhibitors. Participants had either only the EGFR mutation or the latter and the p53 mutation in addition. By analyzing the tumor scans, the researchers confirmed that in patients with only the EGFR mutation, all tumors shrank in response to treatment. But for those with both mutations, while some tumors shrank, others grew. This indicates drug resistance.
Secondly, the researchers studied mice carrying EGFR and p53 mutations. They found that in resistant tumors, more cancer cells had doubled their genomes. They thus had extra copies of all their chromosomes.
The scientists then exposed the lung cancer cells – some with only one EGFR mutation and others with both – to an EGFR inhibitor. They found that within five weeks after drug administration, a significantly higher percentage of cells, with both the double mutation and the double genome, had multiplied into new drug-resistant cells.
“We have shown why having a p53 mutation is associated with poorer survival in patients with non-smoking-related lung cancer. It is the combination of EGFR and p53 mutations that promotes genome doubling. This increases the risk of development of drug-resistant cells due to chromosomal instability”explains Professor Charles Swanton of the UCL Cancer Institute and the Francis Crick Institute in a press release.
Non-small cell lung cancer: despite the two mutations
Faced with their discovery presented in the journal Nature Communications on June 13, 2024, British researchers believe that it would be interesting to screen patients with non-small cell lung cancer with EGFR and p53 mutations. They are therefore working on the development of a common diagnostic test for the two mutations.
“Once we can identify patients with both EGFR and p53 mutations whose tumors show whole genome doubling, we can then treat these patients more selectively. This could mean more intensive monitoring, early radiotherapy or ablation to target resistant tumors, or early use of combinations of EGFR inhibitors, such as osimertinib, with other drugs, including chemotherapy.”explains Dr Crispin Hiley of the UCL Cancer Institute.
