Non-Small Cell Lung Cancer Driven by Several Mutations

Multiple mutations may work together to develop drug-resistant non-small cell lung cancer.

It is commonly thought that most cancers are driven by a single or dominant mutation that can be targeted by drug therapy. New findings may challenge this belief and change the way lung cancer is treated.

The authors of a study published by Nature Genetics discovered that the most aggressive form of lung cancer is actually driven by multiple genetic mutations, which were observed to help cancer progress and avoid targeted drugs.

These findings suggest the need for a new combination for first-line treatment of non-small cell lung cancer (NSCLC) that can address the mutations while preventing drug resistance, according to the study authors.

“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,” said researcher Trever Bivona, MD, PhD. “Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment.”

Despite improved treatments and efforts to outline genetic mutations that drive the disease, lung cancer remains a leading cause of death. Even targeted treatments result in temporary remission, with patients developing drug-resistant disease later on, according to the authors.

“The field has been so focused on treating the ‘driver’ mutation controlling a tumor’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 tumor can take to develop resistance to treatment,” Dr Bivona said. “This could also explain why many tumors are already drug-resistant when treatment is first applied.”

The authors note that the “single-driver” notion for lung cancer has been backed up by multiple genomic studies; however, the well-known studies tend to only focus on mutations in stage 1 disease, which is typically very treatable compared with late-stage disease, according to the study.

“Until recently, our field has relied on genomic data from early-stage cancers, but most of the patients we are treating have stage 4 disease,” Dr Bivona said. “This study is the first in-depth look at the complex genomics of advanced NSCLC, where it turns out that the genetic landscape is wildly different.”

In the new study, the authors analyzed tumor DNA from more than 2000 patients with NSCLC to search for mutations in 73 cancer-causing genes. Of these patients, 1122 had EGFR mutations, while 944 did not have the mutation.

The study showed that 92.9% of tumors had multiple mutations in the cancer-related genes, including EGFR. Tumors had an average of 2 to 3 additional mutations, but the authors noted that some had as many as 13 mutations.

TP53 mutations were observed in more than 50% of tumors. Changes in cancer pathways, including receptor tyrosine kinases, RAS-MAP kinase, PI3 kinase, Wnt/beta-catenin, occurred in 10% of cases, and changes in genes involved with cell division, epigenetic modifications, DNA repair, and signaling pathways occurred in 25% of cases, according to the study.

Additionally, the researchers determined which mutations arose in drug-resistant disease. The authors said that these mutations could be the catalyst for resistance rather than EGFR, according to the study.

An analysis of a subset of patients whose tumor DNA was collected multiple times confirmed the findings and revealed how tumors become more complex and mutated after exposure to targeted drugs, according to the study.

“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,” Dr Bivona said. “In that case, all we’ve done is reshape the landscape of the tumor, perhaps causing temporary remission, but giving ourselves a harder problem to solve when the cancer returns.”

These findings suggest there is an urgent need for novel first-line therapies that target multiple mutations at once, according to the authors.

“We need to go beyond the typical call for combination therapy,” said co-first author Collin Blakely, MD, PhD. “These results shed light on how complex and adaptable these cancers are at a genetic level. Even if you come up with one initially effective combination of drugs, there’s still likely to be a whole slew of other genetic alterations you ultimately need to overcome to kill the cancer. The only way to do that is to adjust your treatment strategy faster than the cancer can evolve resistance.”