Targeting the CIC Protein May Stop Lung Cancer Metastasis

It may be possible to put up a roadblock against metastatic lung cancer. It turns out that lung cancer’s ability to spread may often be due to the inactivation of a single protective protein within tumor cells, according to a study published online November 21, 2016, in Nature Genetics.   

Researchers at UC San Francisco have recently discovered genetic mutations in a protective protein called Capicua (CIC). The scientists demonstrated that there is a disproportionate frequency of mutated CIC in human lung cancers that have metastasized. It was determined that the protein could also be inactivated as a downstream consequence of common biochemical abnormalities that arise in lung cancer, even in cases where the CIC gene itself is not mutated. Some of these abnormalities, thought to drive tumor growth, are already being targeted by both US Food and Drug Administration-approved and experimental drugs in clinical trials.

“We found that this protein, first discovered as a regulator of development in the fruit fly, and also known to direct normal development of air sacs in the lungs, can be co-opted by tumors and inactivated to cause cancers to spread,” said senior study author Trever Bivona, MD, PhD, an associate professor of hematology and oncology and member of the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

Dr. Bivona said there are already treatments in development that might reactivate CIC and stop metastasis. However, he cautioned that more work is warranted to reveal just how effective this strategy may be.

The current study focused on non-small cell lung cancer and the researchers took an unusual and difficult step. They injected fluorescently labeled human lung tumor cells directly into the lungs of mice used to model the disease, instead of beneath the skin or into the tail vein, as is more typical. The scientists tested 11 different CIC mutations identified in human metastatic lung cancers in mice and found evidence that any of these mutations could be a causal factor of metastasis in the human lung cancers.

They analyzed genetic data from hundreds of human lung cancers and found that CIC was mutated in metastatic lung cancer seven times more often than in lung tumors that had not yet spread. The same gene also is often mutated in metastatic gastric cancers.

 Whether caused by genetic mutation or MAPK pathway dysregulation, the researchers found the loss of CIC releases the brakes that hold downstream proteins in check. In the mice, they determined that one of the proteins held in check by CIC (MMP24) is needed for tumors that arise in the lungs to take root at distant body sites, such as bone. Drugs that block overactive MAPK signaling, including a class known as Raf-MEK-ERK inhibitors are already in development. Now, it appears that these drugs may act to stop metastasis by preventing inactivation of CIC.