Two Genes Abnormalities That Cause Squamous Cell Lung Cancer Discovered

For patients with squamous cell lung cancer, the 5-year survival rate stands at only 15%. Because the disease is poorly understood, finding ways to treat the condition has proved problematic. But now, researchers from the Huntsman Cancer Institute at the University of Utah have discovered two gene abnormalities that contribute to the development of the cancer - a discovery they hope will pave the way for new treatment strategies.

The research team, including senior author Trudy Oliver, PhD, an assistant professor of oncological sciences at the university, recently published their findings in the journal Cell Reports.
Squamous cell carcinoma (SCC) lung cancer accounts for 25-30% of all lung cancers. SCC begins in early versions of squamous cells - cells that reside on the inside of the lung's airways. As in all cancers, the cells become out of control and develop mutations that trigger the development of cancerous tumors.
In the case of SCC lung cancer, the researchers wanted to determine what mutations drive the development of cancerous tumors.

Development of mouse model specific to squamous cell lung cancer

The team began by analyzing gene abnormalities that had been discovered in humans with SCC. They found the gene Sox2 is overexpressed in around 60-90% of SCCs and is often present in early tumor development, suggesting that it may trigger cancer. In addition, the researchers found that a tumor suppressor gene - Lkb1 - is mutated in 5-19% of SCCs.
Using this information, the team partnered the overexpression of Sox2 in the lung with the mutated Lkb1 gene in mice. They found that the mice frequently developed SCCs in the lung. This has now provided a mouse model specific to squamous cell lung cancer, which may lead to new treatments for the disease.

The researchers have created a mouse model specific to squamous cell lung cancer, which may lead to new treatments for the disease.

"A pathologist looking under the microscope at our tumors would not know it's from the mouse," says Oliver. "They visually look like human tumors, and then when we stain them for biomarkers of the human disease, our mouse tumors light up for those markers."
"This is the most exciting thing we've done," she adds. "Now that we have a model it unleashes so many questions we can ask to gain a better understanding of the disease."
The researchers point out that at present, there are no drugs that specifically target the Sox2 or Lkb1 genes. But they say there are medications that interrupt the Jak-Stat and mTOR pathways that are believed to be activated by these genes.
These pathways were actually activated in the mouse models, indicating that STAT3 and mTOR inhibitors that block these pathways could be effective against squamous cell lung cancer.
"These are pathways that had not been previously explored for the treatment of squamous tumors because we didn't realize they were important," says Oliver. "That gives us direction for testing the efficacy of drugs aimed at these pathways."
In addition, the researchers note that this mouse model could be used to gain a better understanding of other tumors driven by the Sox2 gene - such as those found in small cell lung cancer - and other SCCs found in brain, esophageal and oral cancers.