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Researchers from UCL, Francis Crick Institute, and AstraZeneca Uncover Key Genetic Mutation Behind Treatment Resistance
A groundbreaking study published in Nature Communications has unveiled a crucial reason why certain non-smoking patients with non-small cell lung cancer (NSCLC) experience poorer outcomes despite targeted treatments. Led by experts from UCL and the Francis Crick Institute, in collaboration with AstraZeneca, the research highlights how specific genetic mutations can lead to treatment resistance and worsened survival rates.
In the United Kingdom, lung cancer ranks as the third most common cancer and the leading cause of cancer-related deaths. While smoking remains a primary risk factor, a significant proportion of patients—particularly those who have never smoked—suffer from NSCLC, which accounts for around 85% of lung cancer cases in the country.
The study focused on mutations within the epidermal growth factor receptor (EGFR) gene, a common driver in NSCLC progression. Typically, treatments targeting EGFR mutations, such as EGFR inhibitors, have shown efficacy in shrinking tumors. However, researchers noted a distinct challenge among patients harboring an additional mutation in the p53 gene—a gene crucial for suppressing tumors.
Professor Charles Swanton, affiliated with both UCL Cancer Institute and the Francis Crick Institute, emphasized, “We’ve demonstrated that the co-occurrence of EGFR and p53 mutations can lead to genome doubling in lung cancer cells. This genomic instability significantly enhances the cancer cells’ ability to resist treatment, thereby worsening patient survival.”
The team re-evaluated data from clinical trials involving osimertinib, a newer EGFR inhibitor, and observed that while tumors with only EGFR mutations responded positively to treatment, those with concurrent p53 mutations exhibited varied responses, including the development of drug resistance. This phenomenon, known as “mixed response,” underscores the complexity in treating NSCLC effectively.
Further investigations using mouse models confirmed that tumors with both mutations and genome doubling were more likely to develop resistance to EGFR inhibitors. This finding suggests a critical need for advanced diagnostic tools capable of detecting genome doubling in clinical settings.
Dr. Crispin Hiley, from UCL Cancer Institute, highlighted the implications for patient care, stating, “Identifying patients with both EGFR and p53 mutations and detecting whole genome doubling could pave the way for tailored treatment strategies. This may involve intensified monitoring, early intervention with radiotherapy or ablation, or the combination of EGFR inhibitors with complementary therapies.”
The study’s findings not only shed light on the underlying mechanisms of treatment resistance in NSCLC but also point towards future advancements in precision medicine. As researchers work towards developing diagnostic tests for genome doubling, the hope is to improve outcomes for a subgroup of lung cancer patients facing significant therapeutic challenges.
For more details on the study, refer to the publication in Nature Communications by Sebastijan Hobor et al., titled “Heterogeneous responses to EGFR tyrosine kinase inhibition in non-small cell lung cancer result from chromosomal instability facilitated by whole genome doubling and TP53 co-mutation.”
Reference:
- Sebastijan Hobor et al. (2024). “Heterogeneous responses to EGFR tyrosine kinase inhibition in non-small cell lung cancer result from chromosomal instability facilitated by whole genome doubling and TP53 co-mutation.” Nature Communications.
