KRAS mutations are prevalent in gastric cancer (GC) and often correlate with therapeutic resistance and unfavorable prognosis. Combined inhibition of MEK and CDK4/6 has shown synergistic antitumor activity in KRAS-mutant GC models, both in vitro and in vivo. Mechanistically, this dual blockade induces autophagy through activation of the AMPK/mTOR pathway, contributing to suppressed tumor proliferation. Notably, combining this strategy with autophagy inhibitors further enhances antitumor effects, suggesting that targeting metabolic adaptability may be therapeutically advantageous.

Concurrently, SQSTM1/p62—an autophagy receptor protein—was found to be overexpressed in GC tissues and positively associated with poor patient prognosis. Functional studies revealed that p62 promotes tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT) by modulating E-cadherin, N-cadherin, and vimentin expression levels. These findings highlight a dual role of autophagy in GC progression, where autophagy induction suppresses tumor growth via metabolic stress, yet elevated p62 expression drives EMT and malignancy.

This review discusses how targeting CDK4/6 and MEK not only disrupts proliferation but also modulates autophagy to inhibit p62-driven EMT. This integrative approach, acting through the AMPK/mTOR pathway, may offer an effective strategy against KRAS-mutant and p62-overexpressing gastric cancers.