Two oncogenes work together to sustain population of cells in lung squamous cell carcinoma

Patients with a common form of lung cancer — lung squamous cell carcinoma — have very few treatment options. That situation may soon change.

A team of cancer biologists at Mayo Clinic in Florida is reporting in the Feb. 10 issue of Cancer Cell the discovery of two oncogenes that work together to sustain a population of cells in lung squamous cell carcinoma, which may be responsible for the lethality of the disease. When these cells, termed cancer stem cells, are inhibited, tumors cannot develop.

"Cancer stem cells are a small population of cells in a tumor that can self-renew and grow indefinitely. They resist most treatments and are thought to be responsible for relapse," says the study's senior author, Alan P. Fields, Ph.D., the Monica Flynn Jacoby Professor of Cancer Studies at Mayo Clinic in Florida.

"If you can shut down cancer stem cells, you may be able to stop relapse after therapy," he says.

The study, which is featured on the cover of Cancer Cell, builds upon years of research by Dr. Fields and his colleagues on a cancer-causing gene protein kinase C iota (PKCiota). They were the first to discover the connection between PKCiota and initiation, promotion and spread of lung cancers, including lung squamous cell carcinoma, which accounts for 30-40 percent of all lung cancer. The researchers found that the PKCiota gene is errantly repeated numerous times in lung squamous cell carcinoma cells through a genetic alteration termed gene amplification. PKCiota gene amplificationis associated with poor patient survival. Subsequently, they discovered that PKCiota is necessary to maintain cancer stem cells in these tumors, but how it did that was not clear.

The newly released study defines the process. The researchers discovered that PKCiota and a second oncogene, SOX2, found in the same region of chromosome 3 known as 3q26, are coordinately amplified and overexpressed in a majority of lung squamous cell carcinomas. The study further shows that these two oncogenes are also functionally linked in these tumors.

"We now know that PKCiota activates SOX2, meaning that these two genes are not just genetically linked by amplification, but also biochemically and functionally linked in promoting lung squamous cell carcinoma," says the study's lead author, Verline Justilien, Ph.D., an instructor of cancer biology at Mayo Clinic in Florida.

The study further shows that PKCiota and SOX2 collaborate to activate a developmental signaling pathway called Hedgehog that maintains lung squamous cell carcinoma stem cells.

The finding is leading to rapid clinical testing. The Mayo team is already testing a drug that targets PKCiota in patients with lung squamous cell carcinoma. And the researchers say that experimental drugs exist to target the Hedgehog signaling pathway as well.

"Our findings indicate that PKCiota and Hedgehog signaling together contribute to cancer stem cell behavior. We believe that targeting these pathways simultaneously may lead to enhanced therapeutic response in lung squamous cell carcinoma patients," says Dr. Fields. The current five-year survival rate of lung squamous cell carcinoma is only 15 percent, he adds.

These findings may have implications beyond lung squamous cell carcinoma. "Gene amplification at 3q26 is one of the most frequent alterations in human cancer, and is often found in many tumors that are difficult to treat, including head and neck and ovarian cancer. This study helps explain what is happening in this region," says Dr. Justilien.

"We are very excited to see whether therapies targeting this pathway work in the clinic," Dr. Fields says. "If successful, this new therapeutic approach may also prove useful in other cancers that harbor 3q26 amplification."