Researchers from UCL, the Francis Crick Institute, and AstraZeneca have discovered why targeted treatment for non-small cell lung cancer is ineffective for certain patients, especially those who have never smoked. The study, published in Nature Communications, reveals that lung cancer cells with specific genetic mutations are more prone to doubling their genome, which enables them to resist treatment.
Resistance to treatment can develop in patients with lung cancer, making it a significant challenge to manage.
In the UK, lung cancer is the third most prevalent type of cancer and the primary cause of cancer-related deaths. About 85% of lung cancer patients have non-small cell lung cancer (NSCLC), which is the most common type among non-smokers. When considered on its own, lung cancer in non-smokers ranks as the fifth most common cause of cancer death globally.
The most frequent genetic mutation in NSCLC is found in the epidermal growth factor receptor gene (EGFR), which enhances the growth of cancer cells. This mutation is present in approximately 10-15% of NSCLC cases in the UK, especially in patients who have never smoked.
The chances of surviving lung cancer vary based on the stage of the cancer. Only about a third of patients with Stage IV NSCLC and an EGFR mutation live for up to three years.
EGFR inhibitors, which target a specific mutation in lung cancer, have been around for over 15 years. While some patients see their tumours shrink with these inhibitors, others, especially those with an additional mutation in the p53 gene, do not respond well and have worse survival rates. Scientists and doctors have not been able to explain this phenomenon.The reason for this is not clear. To understand why, the researchers analyzed data from trials of the latest EGFR inhibitor, Osimertinib, created by AstraZeneca. They examined 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. The team compared every tumor on the scans, which was significantly more than were measured in the original trial. They discovered that for patients with only the EGFR mutations, all tumors got smaller in response to treatment. However, for patients with both mutations, some tumors had shrunk while others had grown.n the context of cancer treatment, the emergence of drug resistance is a concerning issue. This phenomenon, known as a ‘mixed response,’ occurs when certain areas of a cancer are shrinking while others remain unaffected by the treatment. This pattern poses a challenge for physicians who are responsible for the care of cancer patients.
In an effort to understand why some tumors may be more susceptible to drug resistance, a team of researchers conducted a study using a mouse model with specific genetic mutations. Their findings revealed that the resistant tumors in these mice had a higher proportion of cancer cells with duplicated genomes, resulting in extra copies of all their chromosomes.
Subsequently, the researchers administered a treatment Lung cancer cells were studied in the laboratory, some with only the EGFR mutation and some with both mutations, using an EGFR inhibitor. The researchers discovered that after five weeks of exposure to the drug, a higher percentage of cells with both mutations had multiplied into new drug-resistant cells.
Professor Charles Swanton, from UCL Cancer Institute and the Francis Crick Institute, explained: “We have demonstrated why having a p53 mutation is linked to poorer survival in non-smoking related lung cancer patients, as the combination of EGFR and p53 mutations enables genome doubling. This increases the risk of drug resistance, Cells that are resistant to treatment are formed due to chromosomal instability.
Patients with non-small cell lung cancer are currently screened for EGFR and p53 mutations, but there is no standard test for detecting whole genome doubling. 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, explained: “Identifying patients with both EGFR and p53 mutations whose tumors show whole genome doubling will allow for more targeted treatment. This could involve more intensive monitoring, early radiation therapy, or other specific interventions.”
Targeting resistant tumors with therapy or ablation, or using combinations of EGFR inhibitors like Osimertinib early on along with other drugs including chemotherapy are potential strategies to explore.
The Francis Crick Institute provided support for this research, funded in part by Cancer Research UK, the UK Medical Research Council, and Wellcome.
