Jefferson researchers find highly active gene in aggressive human lung cancer

Researchers thought Nit1 might be a tumor suppressor gene — but found it actually promotes cancer growth.

Scientists believe that “conserved” genes — those found in life forms that range from bacteria to plants, insects and humans — perform vital biological functions across species. And limited research on one of those genes, Nitrilase 1 (Nit1), suggested it acts to inhibit cancer development.

But researchers at Sidney Kimmel Cancer Center have found Nit1 is significantly over produced in common lung cancer, compared to normal cells, and that when Nit1 is silenced, growth of lung tumors is suppressed.

Their study, published in the journal Oncotarget, is the first to characterize the contribution of Nit1 to growth and progression of non-small cell lung cancer. The findings strongly suggest that Nit1 may represent a much-needed new target for drug therapy, says the study’s senior researcher, Bo Lu, M.D., Ph.D., radiation oncologist at Jefferson’s Sidney Kimmel Medical College at Thomas Jefferson University.

“Lung cancer in most patients is becoming increasingly resistant to the therapies that exist today, making lung cancer the leading cause of cancer death worldwide,” says Dr. Lu. “There is a critical need for new agents, and an inhibitor of Nit1 may represent a new drug strategy.”

The study is a “nice example of how research designed to understand basic mechanisms in lung cancer can lead to identification of possible new drug targets,” says Adam Dicker, M.D., Ph.D., Chair and Professor of Radiation Oncology, Pharmacology and Experimental Therapeutics at the Sidney Kimmel Medical College of Thomas Jefferson University.

Dr. Lu and his colleagues created mouse models that develop lung cancer due to a KRAS mutation in the presence or absence of Nit1 in the mouse genome . (Human lung cancer with KRAS mutations — about 20-30 percent of all lung cancers — are much more aggressive and difficult to treat.)

Utilizing a mouse model lacking Nit, which was created by a Jefferson researcher, Dr. Jianke Zhang, the scientists then crossbred these mice and found that lack of Nit1 resulted in tumors that were five times smaller than cancer that developed in mice with an active Nit1 gene.

They also found that Nit1 is highly expressed in human lung cancer tissues and cell lines, and that silencing Nit1 in these cancer cells decreased survival of cancer cells.

Investigators then tested whether inhibiting Nit1 could increase the benefit of cisplatin, a commonly used lung cancer chemotherapy, in mice with lung tumors. “The cancer was significantly more sensitive to cisplatin when Nit1 was silenced,” Dr. Lu says. “This is a story of discoveries — a tale of a false assumption that has led to a possible new drug strategy.”

Dr. Lu and his colleagues are continuing to study the mechanisms behind Nit1 expression and inhibition and its potential impact on immune surveillance over lung cancer development.

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