Scientists Discover Crucial Link in the Pathway from Smoke to Lung Cancer

IKBKE, a newly identified gene that is activated by tobacco, could be a fresh target for lung cancer therapies. A new study in the journal Oncogene sheds light on the molecular pathways surrounding the activation of IKBKE, which contributes to lung carcinogenesis.

Patients tend to develop resistance to traditional cancer treatments like chemotherapy and radiotherapy. However, the search for genetic therapy targets could yield individualized, powerful treatments that do not decrease in efficacy. Researchers at Florida’s Moffitt Cancer Center found that, in addition to playing a role in the development of chemoresistance, IKBKE is also part of a carcinogenic molecular pathway that can be set off by tobacco smoke.

The IKBKE gene codes for a serine/threonine kinase protein that is involved in inflammation and in the body’s innate immune response. It is overexpressed in ovarian, breast, and prostate cancers. The IKBKE gene is targeted by STAT3, a transcription factor (a protein that turns genes on and off). Previous studies have established that STAT3 plays an important role in cell growth and death and is known to be affected by tobacco and other environmental carcinogens.

The Moffitt study demonstrates for the first time that IKBKE gene expression levels are influenced by STAT3. The researchers found that direct binding of STAT3 to the promoter region of the IKBE gene caused the gene to produce more RNA and protein. In patient tumor samples, IKBKE and STAT3 levels were positively correlated and levels were associated with smoking history; patients who smoked more had higher levels of both proteins. The expression of IKBKE also increased when nicotine or a related compound, NNK, was administered to cell cultures. These high expression levels were abolished when STAT3 was knocked out, indicating that STAT3 is the crucial link in the tobacco carcinogenic pathway.

The overexpression of IKBKE in the presence of tobacco carcinogens may not just promote cancer growth—it may also stifle its treatment. Cells expressing IKBKE became resistant to the chemotherapeutic agents cisplatin, gemcitabine, and doxorubicin, which normally cause cancer cell death. When expression levels were decreased by a gene knockdown of IKBKE, cells were once again sensitive to chemotherapy. IKBKE thus mediates the survival of tobacco-induced lung cancer cells and represents a potential new therapeutic target.

According to the study’s authors, the low survival rate of approximately 15% for non-small cell lung cancer (NSCLC) patients and the development of drug resistance must be addressed by the discovery of new drugs and therapies. STAT3 and IKBKE are attractive targets because they are tobacco-induced and are involved in chemoresistance. This study is the first to connect the dots between IKBKE and tobacco use in NSCLC; it also reveals the molecular regulation that creates a cancer-friendly inflammatory environment and promotes cancer cells via chemoresistance.