Lung Cancers Driven by Multiple Mutations
A new study challenges the previously held belief that most cancers were the result of a single, dominant genetic variant, typically known as a ‘driver’ mutation. Not only could this affect the way we think about cancers, but it also suggests that the idea of developing a single pharmaceutical agent to target the driver mutation will not be successful. The study, led by researchers at the University of California San Francisco in conjunction with Guardant Health, was reported in Nature Genetics earlier this week.
“Currently, we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment,” said Trever Bivona, MD, PhD, Oncologist at UCSF Medical Centre and Associate Professor in Haematology and Oncology.
Lung cancers are the leading cause of cancer deaths in the world. One of the reasons for this is that many current drug treatments are unable to prevent the cancer from returning, at which point it will likely have developed resistance to the previously used agents. This is made worse by the fact that many of the research projects currently studying lung cancer are primarily working with stage 1 cancer samples, which differ significantly from more advanced cancers.
To try to better understand advanced non-small cell lung cancer, the team analysed tumour DNA data from more than 2,000 patients with the disease. Using a clinically approved liquid biopsy test from Guardant Health, they searched for mutations in 73 cancer-associated genes in tumour data from 1,122 patients with an EGFR mutation and 944 without one.
They found that 92.9% of those patients were carrying an average of 2-3 extra mutations beyond EFGR and, in some cases, there were as many as 13 extra mutations. The most common secondary mutation was in the TP53 gene, which was mutated in more than half of the participants. Between 10% and 25% were also found to have mutations in ‘traditional’ cancer-associated genes, such as MAP kinases, receptor tyrosine kinases, and genes linked to cell division and DNA repair.
“The field has been so focused on treating the ‘driver’ mutation controlling a tumour’s growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumour can take to develop resistance to treatment,” said Dr. Bivona. “This could also explain why many tumours are already drug-resistant when treatment is first applied.”
The team were also able to demonstrate how non-small cell lung cancer could become more genetically complex following treatment, by testing multiple samples taken from the same patient over the course of their treatment. It is this adaptability that allows the cancer to return after a patient has gone into remission and how drug resistance to targeted therapies can develop.
“The implication of this work is that a drug targeted at the EGFR mutation may be able to wipe out the cells carrying that mutation alone, but they leave behind – and may even enhance – cells with other, additional mutations,” said Dr. Bivona. “In that case, all we’ve done is reshape the landscape of the tumour, perhaps causing temporary remission, but giving ourselves a harder problem to solve when the cancer returns.”