Certainly, tobacco is by far the leading cause of lung cancer. However, non-smokers can also suffer from it. In fact, nearly 10% of bronchopulmonary cancers occur in these patients. Moreover, this trend has been increasing in recent years, especially among young people and women, probably due to air pollution potentially combined with genetic and lifestyle factors. Unfortunately, for these patients, they often do not respond well to treatment targeting non-small cell lung cancer. But how can this be explained, and why are some lung cancers more difficult to treat than others?

In their study published on June 13 in the journal Nature Communications, researchers from the University College of London explain that they have identified two genetic mutations within cancer cells that make them more resistant to treatment.

Lung cancer: two mutations at work

Identified in mice and in vitro, the mutations in question concern the EGFR gene, which promotes cell growth, and TP53, involved in regulating cell division and preventing tumors. It is important to note that in the case of non-small cell lung cancer (NSCLC), which represents between 80 and 85% of malignant lung tumors and is most common in non-smokers, the treatment used for the past fifteen years generally targets the EGFR mutation, a known risk factor. However, this approach does not work for all patients, which is why scientists from the Cancer Institute and the Francis Crick Institute at the University College of London decided to study these mutations more closely in the hopes of understanding why treatment responses can vary so much.

By comparing scans of patients treated with Osimertinib, an EGFR inhibitor, the scientific team eventually realized that if patients only had an EGFR mutation, it helped reduce tumor size and improve patients’ prognosis. However, when an additional TP53 mutation was added, the results became much more nuanced. While some tumors did indeed shrink, researchers also observed in other cases a growth, indicating resistance and a mixed response to the medication, which can complicate the task for oncologists treating patients. Subsequently, in mice carrying EGFR and p53 mutations with resistant tumors, scientists noted that a greater number of cancer cells had doubled their genome, thus possessing additional copies of all their chromosomes.

“We have shown why having a p53 mutation is associated with lower 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 developing drug-resistant cells due to chromosomal instability,” summarizes Professor Charles Swanton of the UCL Cancer Institute and the Francis Crick Institute in a statement.

Credits: Mohammed Haneefa Nizamudeen/iStock

A discovery that could ultimately improve patient treatment

Currently, there is no test to detect this double mutation. However, scientists are working on developing a new diagnostic tool with the hope of improving the survival rate of patients.

“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 the early use of combinations of EGFR inhibitors, such as osimertinib, with other drugs, including chemotherapy,” says Dr. Crispin Hiley of the UCL Cancer Institute.

You can find the detailed study on this link.

In conclusion, the findings of this study shed light on the complexities of treating lung cancer, especially in non-smokers, and provide insights that could lead to more personalized and effective treatment strategies in the future. By understanding the genetic mutations that contribute to treatment resistance, healthcare professionals can better tailor therapies to individual patients, ultimately improving outcomes and survival rates.