Scientists have discovered why targeted therapy for non-small cell lung cancer fails in some patients, especially those who have never smoked.
The study, published in the journal Nature Communications, showed that lung cancer cells that contain two specific genetic mutations are more likely to duplicate their genome, which helps them tolerate treatment and develop resistance to it.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer among patients who have never smoked. Non-smoking-related lung cancer is the fifth most common cause of cancer death in the world.
The most common genetic mutation found in non-small cell lung cancer is in the epidermal growth factor receptor (EGFR) gene, which enables cancer cells to grow faster.
Survival rates for people with non-small cell lung cancer vary depending on how advanced the cancer is, with about a third of patients with stage IV of this cancer and an EGFR mutation living for up to three years.
It is noteworthy that lung cancer treatments that target this mutation, known as EGFR inhibitors, have been available for more than 15 years. However, while some patients see their cancer tumors shrink with EGFR inhibitors, other patients, especially those with an additional mutation in the p53 gene (which plays a role in tumor suppression), fail to respond and experience much worse survival rates. But scientists and doctors have not yet been able to explain why this happens.
To find the answer, researchers from University College London, the Francis Crick Institute and AstraZeneca reanalyzed data from trials of the newest EGFR inhibitor, osimertinib, developed by AstraZeneca.
The researchers looked at baseline scans and first follow-up scans performed a few months after treatment for patients with only EGFR mutations or with both EGFR and p53 mutations.
They found that for patients with only EGFR mutations, all tumors became smaller in response to treatment. But for patients with both mutations, while some tumors shrank, others grew, providing evidence of rapid drug resistance.
This pattern of response, when some, but not all, areas of the cancer shrink in response to drug treatment within an individual patient, is known as a “mixed response,” and poses a challenge to oncologists who care for cancer patients.
To investigate why some of these patients' tumors were more susceptible to drug resistance, the team next studied a mouse model containing an EGFR and p53 mutation. They found that within the resistant tumors in these mice, much larger numbers of cancer cells had duplicated their genomes, giving them extra copies of all of their chromosomes.
Next, the researchers treated lung cancer cells in the laboratory, some with one EGFR mutation and some with both, with an EGFR inhibitor. They found that within five weeks of exposure to the drug, a much higher proportion of cells with the double mutation and double genomes multiplied into new drug-resistant cells.
Professor Charles Swanton, from the University College London Cancer Institute and Francis Crick Institute, said: 'We have shown why the presence of a p53 mutation is associated with poor survival in patients with non-smoking-related lung cancer, a combination of EGFR and p53 mutations. This allows the genome to be duplicated, which increases the risk of drug-resistant cells developing through chromosomal instability.