Abstract 3040: Memantine, (a dual α7-nAChR/NMDAR antagonist) displays anti-tumor activity in human squamous cell lung cancer

Abstract Purpose of the study: Squamous cell lung carcinoma (LUSC), also called epidermoid carcinoma, is a type of non-small cell lung cancer (NSCLC) that typically develops in one of the air passages, or bronchi, of the lungs. It is the second most common type of NSCLC and accounts for roughly 30 percent of all lung cancer cases. The development of LUSC bears an 85% correlation with smoking habits. Nicotine, the addictive component of cigarettes, promotes the growth and progression of lung cancers via the α7-nicotinic acetylcholine receptor (α7-nAChR) subunit in human lung cancer cells. Published reports show that the α7-nAChR is over expressed on LUSCs relative to normal lung epithelial cells. Therefore, agents which block the function of α7-nAChR should inhibit the growth of human LUSC cells. The drug memantine is a dual α7-nAChR/NMDAR antagonist which is used clinically to combat dementia associated with mild -to-moderate Alzheimer’s disease in patients. Receptor binding assays have shown that the affinity of memantine for α7-nAChR receptors is greater than that of NMDARs. The primary objective of our study was to determine the anti-cancer activity of memantine in human LUSC. Experimental procedures. The expression of α7-nAChR on human LUSC cells was analyzed by ELISA. The effect of memantine of nicotine-induced proliferation of LUSC cells was measured by Proliferating Cell Nuclear Antigen (PCNA) ELISA assays. The growth-inhibitory activity of memantine was confirmed in chicken chorioallantoic membrane (CAM) model systems of LUSC. Next, the anti-tumor activity of memantine was measured in two independent mice models, namely the cell derived xenograft (CDX) mouse model and the patient derived xenograft (PDX) mouse model. Finally, siRNA methodology was used to delineate the signaling pathways underlying the anti-proliferative activity of memantine. Results: Memantine displayed robust anti-proliferative activity in a panel of human LUSC cell lines. The anti-proliferative activity of memantine was also observed in chicken CAM models of LUSC. The treatment of LUSC cells with memantine induced cell cycle arrest at G1/S phase. Finally, the administration of memantine via dietary methods decreased nicotine-induced growth of LUSC tumors in both CDX and PDX tumors in immunodeficient mice models. Conclusions: The drug memantine could be repurposed for the treatment of LUSC in patients. Support or Funding Information: Funding for our study was supported by an NIH R15-AREA Grant (2R15CA161491-02), Edwards Cancer Center Pilot grant, Cabell Huntington Hospital, Marshall University. This work was supported in part by the West Virginia IDeA Network of Biomedical Research Excellence (WV-INBRE) grant GM103434 (PI: Dr. G. Rankin). Citation Format: Javan C. Christian, Krista L. Denning, Kushal J. Modi, Reagan S. Light, Sarah L. Miles, Yi Charlie Chen, Piyali Dasgupta. Memantine, (a dual α7-nAChR/NMDAR antagonist) displays anti-tumor activity in human squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3040.