Mayo researchers find two oncogenes that drive common lung cancer

Volume 3, Issue 2, 2014


New therapies targeting these oncogenes may prevent tumors from developing, Mayo Clinic researchers find.

Photograph of Alan P. Fields, Ph.D., the Monica Flynn Jacoby Professor of Cancer Studies at the Mayo Clinic Cancer Center in Florida

Alan P. Fields, Ph.D.

Patients with lung squamous cell carcinoma, a common form of non-small cell lung cancer, have very few treatment options. However, that situation may soon change thanks to the work of a team of cancer biologists at the Mayo Clinic Cancer Center in Florida.

The researchers published a paper in the Feb. 10, 2014, online edition of the journal Cancer Cell about 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, called cancer stem cells, are inhibited, tumors can't 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," said the study's senior author, Alan P. Fields, Ph.D., the Monica Flynn Jacoby Professor of Cancer Studies at the Mayo Clinic Cancer Center in Florida. "If you can shut down cancer stem cells, you may be able to stop relapse after therapy."

The lung cancer study builds on 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 to 40 percent of all lung cancers.

The researchers found that the PKCiota gene is errantly repeated numerous times in lung squamous cell carcinoma cells through a genetic alteration called gene amplification. PKCiota gene amplification is associated with poor patient survival.

The researchers subsequently discovered that PKCiota is necessary to maintain cancer stem cells in these tumors, but how it did that wasn't clear. The lung cancer study defines the process.

Researchers discovered that PKCiota and a second oncogene, SOX2, found in the same region of chromosome 3 known as 3q26, are both amplified and overexpressed in a majority of lung squamous cell carcinomas. The study also 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," said the study's lead author, Verline Justilien, Ph.D., an instructor of cancer biology at Mayo Clinic in Florida.

The study also 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 study 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," Dr. Fields said. "We believe that targeting these pathways simultaneously may lead to enhanced therapeutic response in lung squamous cell carcinoma patients."

Watch a video of Dr. Fields discussing this study.