X-ray of lung showing chest cancer
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Targeted treatment for non-small cell lung cancer (NSCLC) sometimes fails to work, even in patients who have never smoked. The reason, new research suggests, hangs on two mutations in the EGFR and TP53 genes. Patients with mutations in these two genes are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone, according to new work by researchers from University College (UCL), the Francis Crick Institute, and AstraZeneca. 

Charles Swanton, from UCL Cancer Institute and the Francis Crick Institute, said: “We’ve shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer, which is the combination of EGFR and p53 mutations enabling genome doubling. This increases the risk of drug-resistant cells developing through chromosomal instability.”

Their study was recently published in Nature Communications and the first author is Sebastijan Hobor.

According to WHO, lung cancer is the leading causes of cancer death in the world. Around 85% of patients with lung cancer have NSCLC, and this is the most common type found in patients who have never smoked. Considered separately, “never smoked” lung cancer is the fifth most common cause of cancer death in the world.

The most common genetic mutation found in NSCLC is in the epidermal growth factor receptor gene (EGFR), which enables cancer cells to grow faster. It is particularly common in patients who have never smoked. Survival rates vary depending on how advanced the cancer is, with only around a third of patients with Stage IV NSCLC and an EGFR mutation surviving for up to three years.

EGFR inhibitors have been available for over 15 years. However, while some patients see their tumors shrink with EGFR inhibitors, other patients, particularly those with an additional mutation in the p53 gene (which plays a role in tumor suppression), fail to respond and experience far worse survival rates. But scientists and clinicians have so far been unable to explain why this is the case.

To find the answer, the researchers re-analyzed data from trials of the newest EGFR inhibitor, Osimertinib, developed by AstraZeneca. They looked at baseline scans and first follow-up scans taken a few months into treatment for patients with either EGFR-only or with EGFR and p53 mutations.

They found that for patients with just the EGFR mutations, all tumors got smaller in response to treatment. But for patients with both mutations, while some tumors shrank others had grown, providing evidence of rapid drug resistance.

The team then studied a mouse model with both the EGFR and p53 mutation. They found that within resistant tumors in these mice, far more cancer cells had doubled their genome, giving them extra copies of all their chromosomes.

UCL’s Crispin Hiley told Inside Precision Medicine, “The chromosomes are copied as a normal part of cell division. But following the copying of the chromosomes the cell doesn’t divide. That means a cell has at least twice an many copies of a chromosome as a ‘normal cell’.”

The researchers then treated lung cancer cells in the lab, some with just the single EGFR mutation and some with both mutations, with an EGFR inhibitor. They found that within five weeks of exposure to the drug, a significantly higher percentage of cells with both the double mutation and double genomes had multiplied into new drug-resistant cells.

NSCLC patients are already tested for EGFR and p53 mutations, but there is currently no standard test to detect the presence of whole genome doubling. The researchers are already looking to develop a diagnostic test for clinical use.

Hiley said, “Once we can identify patients with both EGFR and p53 mutations whose tumors display whole genome doubling, we can then treat these patients in a more selective way.”

He added that, “There are some new an exciting treatments for lung cancer that have been presented at recent conferences (ASCO2024, ESMO2023 – eg MARPOSSA trial) but there are lots of side effects for patients and we think these additional treatments might be most approiate for patients with EGFr, TP53 and whole genome doubling.”

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