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03-06-2013 | Respiratory | Article

Nicotine-induced changes alter EGFR-TKI efficacy


Free abstract

medwireNews: Japanese scientists have uncovered a mechanism by which smoking reduces the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with lung cancer.

Using non-small-cell lung cancer (NSCLC) cells lines, the researchers found that the α1 nicotinic acetylcholine receptor (nAChR) subunit mediates chronic nicotine-induced resistance to EGFR-TKI treatment using multiple cellular pathways.

"Given the potential role of α1 muscle-type nAChR in several of the important pathways, targeted inhibition of α1 nAChR might become a novel treatment in NSCLC," suggest Koichi Takayama (Kyushu University, Higashiku, Fukuoka) and co-workers.

"In addition, the notion that α1 nAChR functions to promote lung carcinogenesis raises questions regarding the safety and appropriateness of nicotine-replacement therapies," they say.

As reported in the Journal of Thoracic Oncology, α1 nAChR mediated nicotine-induced phosphorylation of the ERK1/2 and Akt (Ser-473) pathways, involved in promotion of cell growth and survival, and nicotine-induced production of EGFR and phosphorylated EGFR.

Pretreating NSCLC cells with nicotine 24 hours before treatment with a EGFR-TKI significantly reduced the agent's efficacy, while a month's treatment resulted in resistance of up to 20 umol. When α1 nAChR was silenced in the resistant cells using RNA, resistance was significantly reduced, indicating that long-term nicotine-induced EGFR-TKR resistance is at least partly reliant on α1 nAChR expression.

"As smoking cessation is the most effective way to prevent nicotine-induced EGKR-TKI resistance, the study gives us a substantial reason to advocate smoking cessation for the cancer patients who smoke," Takayama et al emphasize.

They believe that future research should "address the question of whether lung cancer risk is directly influenced by α1 nAChR or indirectly influenced by smoking behaviors; the effects of cigarette exposure on the pharmacokinetics involved in the EGFR-TKI resistance actions should also be raised."

"Moreover, other nAChR subunit genes in chronic nicotine exposure warrant further evaluation," the team adds.

medwireNews ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

By Lynda Williams, Senior medwireNews Reporter

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