Researchers have found that people who have never smoked are less likely to respond to standard treatment for non-small cell lung cancer, due to a combination of two genetic mutations that make cancer cells in non-smokers more resistant to treatment. These findings were published in the journal Nature Communications. While smoking is the leading cause of lung cancer, 10% to 20% of people who get lung cancer have never smoked, according to the CDC. The causes of lung cancer among non-smokers are unclear, with environmental, genetic, and lifestyle factors potentially playing a role. Lung cancer among non-smokers is a significant cause of death worldwide.
Non-smokers who develop non-small cell lung cancer are often resistant to standard treatment, with genetic mutations potentially being the cause. The combination of mutations in the epidermal growth factor receptor gene (EGFR) and the p53 gene result in drug-resistant tumors, with only about a third of people with these mutations surviving up to three years. Targeted treatment typically involves EGFR inhibitors, but tumors in people with both mutations may grow after treatment. Additionally, some tumors may have more cancer cells that have doubled their genome, leading to drug-resistant cells through chromosomal instability.
Researchers noted that there is currently no test available to detect the dangerous genome doubling seen in some non-small cell lung cancer patients. However, work is underway to develop a test that can identify patients with both EGFR and p53 mutations whose tumors display whole genome doubling. This information can help in treating patients more selectively with strategies such as combination therapies, like osimertinib in combination with chemotherapy or bispecific antibodies targeting EGFR and MET. These therapies aim to prevent the emergence of resistance to treatment.
New therapies can be tailored to address non-small cell lung cancer cases where EGFR inhibitors are ineffective. When targeted treatments stop working, physicians may conduct molecular testing to determine new mutations in the tumor, which can inform appropriate interventions to overcome resistance mechanisms. For example, patients with EGFR mutation may develop new mutations like C797S, for which there are experimental drugs in clinical trials that can overcome the resistance. The proportion of lung cancers in individuals who have never smoked has increased, particularly among women and younger age groups. Women who have not smoked are more than twice as likely to develop lung cancer compared to men who have never smoked.
Overall, the findings from this study shed light on the challenges faced by non-smokers with non-small cell lung cancer in responding to standard treatment due to genetic mutations. Developing new diagnostic tests to detect genome doubling and targeted therapies to address treatment-resistant cases is crucial in improving outcomes for these patients. More research and clinical trials are needed to further understand the mechanisms behind drug resistance and to tailor treatment strategies for non-smokers with lung cancer.
