Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors

Table 1 Targeted therapeutic strategies against the phosphatidylinositol 3-kinase/protein kinase B pathway in gastrointestinal cancers

Target type	Representative agents	Mechanism of action	Applicable tumor types
Genetic vulnerability targeting	ARID1A-deficient subtype (GC)	Synthetic lethality via PI3K/AKT hyperactivation	GC (30% mutation prevalence)
Small-molecule inhibitors	LY294002	Suppression of ZDHHC20-mediated HCC progression by blocking PI3K catalytic activity	HCC
Combination therapy	EGFR inhibitor + PI3K inhibitor	Synergistic inhibition of autophagy-dependent drug resistance	Colorectal cancer/head and neck squamous cell carcinoma
Natural compound synergy	Astragalus polysaccharide + radiotherapy	Radiosensitization through AKT inhibition and enhanced DNA damage response	Gastrointestinal tumors (adjuvant therapy)

ARID1A: AT-rich interaction domain 1A; GC: Gastric cancer; PI3K: Phosphatidylinositol 3-kinase; LY294002: PI3K inhibitors; AKT: Protein kinase B; ZDHHC20: Zinc finger DHHC-type containing 20; HCC: Hepatocellular carcinoma; EGFR: Epidermal growth factor receptor.