Gene linked to some smokers’ lung cancer

An overproduced receptor protein that shows up in a subset of lung cancers may offer a target of opportunity for new drugs and a glimmer of hope for some patients, researchers report.

Excess amounts of a protein known as FGFR1, or fibroid growth factor receptor 1, often show up in smokers who develop a hard-to-treat form of lung cancer, suggesting that tobacco smoke exposure damages the gene encoding this protein and steers cells toward cancer in some people. Researchers report the findings in the Dec. 15 Science Translational Medicine.

Scientists have been investigating the four known FGFR genes for years, and defects in these genes have been linked to cancer of the lung, bladder, uterus, breast and blood, says Lynn Heasley, a physician and researcher at the University of Colorado Denver Anschutz Medical Campus in Aurora who wasn’t part of this study. “This is the first paper where you actually see amplification of the gene in primary [lung] tumors. In that way, it’s an important advance.”

In gene amplification, multiple copies of a defective gene appear and the gene’s protein is overproduced, altering its effect on the cell’s processes. Several research groups have plans to test drugs that inhibit FGFR proteins in cancer patients whose tumors have the gene amplification.

In the new study, the researchers concentrated on squamous cell carcinoma of the lung, a deadly malignancy responsible for about one-fourth of lung cancers. It mainly hits smokers. Analysis of squamous cell tumors from 155 lung cancer patients showed that 15 had a defective FGFR1 gene. Of those 15 patients, 11 were current or former smokers, and data were unavailable for the other four. 

The researchers then used a different technique to analyze samples of 153 other squamous cell lung tumors and found that the FGFR1 gene was amped up in 22 percent of them. But the defect turned up in only 1 percent of 581 nonsquamous cell lung tumors included in a publicly available database.

The scientists also tested an FGFR-inhibiting compound called PD173074 against 83 lung cancer cell lines. The compound blocked growth and caused cancer cell death in four of the cell lines, and three of those had an altered FGFR1 gene. When the scientists tested the compound on mice with squamous cell lung cancer, the animals whose tumors had a defective FGFR1 gene benefited from the treatment, showing marked tumor shrinkage.

The compound used in this study is unstable and probably won’t be suitable for people, says study coauthor Roman Thomas, physician and researcher at the Max Planck Institute for Neurological Research and the University of Cologne in Germany. But drug manufacturers, including Novartis and AstraZeneca, have developed other FGFR inhibitors aimed at treating patients.

Early-stage clinical trials of those FGFR inhibitors are recruiting breast cancer patients. Thomas and his colleagues are planning to test an FGFR inhibitor in lung cancer patients who screen positive for the altered FGFR1 gene.

“We’re still in the early days here,” Heasley says, but  FGFR inhibitors might hold potential as drugs that can be aimed at tumors that arise in smokers.

Lung cancer takes the largest toll of all malignancies, killing more people than breast, prostate and colon cancer combined. While often treatable when it appears in nonsmokers, fewer options are available for squamous cell lung cancer and other forms that are more common among smokers.