Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies

Abstract

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is an ion-gated calcium channel that plays a significant role in various aspects of cancer pathogenesis, particularly in lung cancer. Preclinical studies have elucidated the molecular mechanism underlying α7 nAChR-associated lung cancer proliferation, chemotherapy resistance, and metastasis. Understanding and targeting this mechanism are crucial for developing therapeutic interventions aimed at disrupting α7 nAChR-mediated cancer progression and improving treatment outcomes. Drug research and discovery have determined natural compounds and synthesized chemical antagonists that specifically target α7 nAChR. However, approved α7 nAChR antagonists for clinical use are lacking, primarily due to challenges related to achieving the desired selectivity, efficacy, and safety profiles required for effective therapeutic intervention. This comprehensive review provided insights into the molecular mechanisms associated with α7 nAChR and its role in cancer progression, particularly in lung cancer. Furthermore, it presents an update on recent evidence about α7 nAChR antagonists and addresses the challenges encountered in drug research and discovery in this field.

Figure 1

Schematic representation of the molecular mechanism underlying the association between the α7 nicotinic acetylcholine receptor (nAChR) and cancer progression. N; nicotine and its derivatives (created using Biorender.com).

Figure 2

α7 nAChR orthosteric binding pocket and pharmacophore of α7 nAChR ligands. CC: cationic center; HA: hydrogen bond acceptor; HP: hydrophobic part.

Figure 3

Structure of the α7 nAChR antagonists.