The PI3K-AKT Signaling Axis Modulates Gastric Cancer Cell Proliferation and Multidrug Resistance

Abstract

Worldwide, GC ranks among the top five most commonly diagnosed cancers, with its incidence and mortality rates remaining at a high level for a long time. Patients with advanced GC often lose the opportunity for surgical resection due to disease spread, and their treatment relies heavily on systemic chemotherapy and local radiotherapy. However, patients still tend to experience a decline in therapeutic efficacy during the treatment cycle and eventually fall into the dilemma of treatment failure, with MDR being the core cause of this outcome. A large number of studies have shown that the PI3K/AKT pathway plays a crucial role in tumor drug resistance, through mechanisms including inhibiting apoptotic pathways, promoting tumor growth, and regulating tumor metabolism. This review focuses on the specific pathways by which the aberrant activation of the PI3K/AKT axis regulates MDR in GC—including the modulation of autophagy, enhancement of drug efflux, promotion of anti-apoptotic responses, and suppression of ferroptosis in cancer cells. It also summarizes key MDR-related targets within this pathway (encompassing proteins such as NF-κB, mTOR, and NRF2) and further explores how the dysregulated PI3K/AKT pathway influences tumor resistance from both chemotherapy and radiotherapy perspectives. The ultimate aim of this article is to provide a novel and comprehensive theoretical framework for the application of PI3K/AKT axis inhibitors in GC combination therapy strategies.