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Researchers Find Potential Target for Treating Tobacco-Associated NSCLC

Oncogene inhibitor looks promising (Feb. 14)

Researchers at the Moffitt Cancer Center in Tampa, Fla., have found a potential targeted therapy for patients with tobacco-associated non–small-cell lung cancer (NSCLC). It is based on the newly identified oncogene IKBKE, which helps regulate the immune response.

The IKBKE gene is part of a family of enzyme complexes involved in increasing cellular inflammation. IKBKE over-expression has been associated with breast and prostate cancers. However, it had not been linked to an environmental carcinogen, such as tobacco smoke, until now. Tobacco smoke is the strongest documented initiator and promoter of lung cancer. The traditional model holds that tobacco components promote carcinogenesis through a process that leads to DNA damage.

Recent studies have shown that tobacco smoke can also promote lung cancer through changes in the pathways that regulate cell proliferation and survival. The new research explored identifying and understanding one of these signaling pathways in order to find potential drug targets to treat NSCLC.

In the new study — published in Oncogene — IKBKE was found to be induced by two tobacco carcinogens: nicotine and a nicotine-derived nitrosamine ketone found in tobacco smoke. The findings suggest that IKBKE is a key molecule related to tobacco-induced lung cancer.

“Since IKBKE kinase is induced by tobacco, small-molecular inhibitors of IKBKE could have a therapeutic drug potential for lung cancer,” said lead author Jin Q. Cheng, PhD, MD.

Current treatments for NSCLC include surgery, radiotherapy, and chemotherapy. However, patients eventually develop resistance to treatment. There is a need to better understand the molecular mechanism of resistance and to develop new gene-targeted therapies that can circumvent resistance, the authors said.

In the new study, the researchers also reported for the first time that IKBKE is a target of STAT3 — a transcription factor that plays a key role in many cellular processes, such as cell growth and apoptosis.

According to the researchers, STAT3 is often activated in various types of human cancers. When activated, it increases IKBKE over-expression and protein levels. In NSCLC, nicotine-induced IKBKE depends on STAT3.

The authors noted that the activation stage of STAT3 has an attractive therapeutic potential because IKBKE is a STAT3 target. While IKBKE induces chemotherapy resistance, reducing IKBKE sensitizes cancer cells to chemotherapy and reduces cancer cell survival.

“Since the IKBKE kinase over-expression is induced by tobacco smoke and IKBKE levels increase in response to nicotine and nicotine-derived nitrosamine ketone, this evidence can be potentially used to develop a non–small-cell lung cancer intervention strategy that targets IKBKE,” Cheng concluded.

Source: Moffitt Cancer Center; February 14, 2013.

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