Growth factor receptor gene amplification may explain smokers' squamous lung cancer

The key to effective treatment of squamous lung cell lung cancer in smokers may be at hand.

Unlike the mutations that underlie treatments for lung adenocarcinomas, the genetic underpinnings of squamous cell lung cancer, the kind of cancer that affects smokers, have not been known until now. While creating genomic profiles of a large set of lung cancer cells, an international research team led by Roman Thomas, M.D., have unmasked a possible culpring: the fibroblast growth factor receptior 1 (FGFR1) gene.

The team discovered that squamous cell lung cancer samples contained more copies of the FGFR1 gene than other cancer types. Detailed research revealed that more than 20% of squamous cell lung cancer samples taken from patients with the disease harbored multiple copies of FGFR1. Dr. Thomas and colleagues then determined that a molecule that broadly inhibits FGFR1 gene function could block growth and cause cell death in squamous cell lung cancers that contained many copies of the FGFR1 gene. They reported the FGFR1-squamous cell cancer link in Science.

“In our opinion, the discovery is extremely significant because we identified the first genetic alteration with an immediate therapeutic implication in squamous-cell lung cancer, a frequent subtype of lung cancer for which no specific treatment exists,” said Dr. Thomas, a principal investigator at the Max Planck Institute for Neurological Research. “While in lung adenocarcinomas of ‘never smokers’, EGFR mutations and EML4-ALK fusions were found that represent therapeutic targets, no such alteration has so far been described in squamous-cell lung cancer. The second aspect is that the amplification is really frequent; we found it to occur in up to 20% of all squamous-cell lung cancer patients.”

Their suspicions that FGFR1 might be the key to reining in at least some smokers’ lung cancers grew after the research team advanced to studies on a mouse model of squamous cell lung cancer. The team, based in Cologne, Germany, found that tumors shrank in the murine model in response to an inhibitor of the FGFR1 gene.

Importantly, the researchers also found that tumors bearing the FGFR1 amplification were dependent on the activity of the FGFR1 protein. This is why inhibiting FGFR1 in such tumors in mice led to tumor regressions.

Next year Dr. Thomas and colleagues will conduct the ultimate test, a clinical trial to determine the effects of a drug designed to target the FGFR1 gene. The trial will begin in February 2011 at several sites, including the cancer center associated with the Max Planck Institute.

Dr. Thomas said he could not reveal the name of the compound or the company that makes it. He was more than happy, however, to describe the importance of the work leading up to the trial.

“The hope is that the patients whose tumors bear the amplification will experience tumor shrinkage upon treatment with FGFR inhibitors,” he said. “Thus, FGFR1 would be the first case of personalized medicine in squamous-cell lung cancer of smokers.”