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.

Table 2 Core mechanisms of Osteopontin-phosphatidylinositol 3-kinase/protein kinase B axis in malignant progression

Mechanistic category	Key molecules/pathways	Functional outcomes	Associated cancers
Promotion of proliferation & survival	Integrin receptors, BAD/Bcl-2, PI3K/AKT/mTOR	Inhibition of apoptosis; Upregulation of MMP-2/VEGF; Enhanced cell survival	GC, pancreatic cancer
Induction of EMT & metastasis	E-cadherin, Snail, Twist, EGFR/PI3K/AKT	Loss of epithelial markers; Activation of mesenchymal programs; Enhanced invasiveness	HCC, NSCLC
Remodeling tumor microenvironment	CAFs, VEGF, IL-8, CXCL11/POSTN	Angiogenesis; Immune suppression; CSC enrichment; Stromal activation	GC, colorectal cancer

PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; EGFR: Epidermal growth factor receptor; CAFs: Cancer-associated fibroblasts; VEGF: Vascular endothelial growth factor; CXCL11: C-X-C motif chemokine ligand 11; POSTN: Periostin; EMT: Epithelial-mesenchymal transition; MMP-2: Matrix metalloproteinase 2; CSC: Cancer stem cells; NSCLC: Non-small cell lung cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma.

Table 3 Osteopontin-mediated therapeutic resistance mechanisms and interventions

Mechanism category	Key molecules/pathways	Functional effects	Intervention strategies	Related cancers
Chemoresistance	PI3K/AKT/mTOR, NEMO-ATM/IKKα, DNA repair pathways	Enhances DNA damage repair; Reduces sensitivity to 5-FU/radiotherapy	Wortmannin (PI3K inhibitor), PRDM15 knockout	Colorectal cancer
Targeted therapy resistance	HER2/EGFR, PI3K/AKT-EMT, DTL	Inhibits trastuzumab efficacy; Activates EMT; Upregulates pro-survival genes (e.g., Bcl-2)	OPN-neutralizing antibodies, LY294002	GC, HCC, pancreatic cancer
Autophagy-mediated resistance	OPN/NF-κB, DRP1, LC3-II/p62	Sustains chemoresistance via autophagic flux blockade	Liensinine (autophagy inhibitor), DRP1 activation	Lung adenocarcinoma
Immune evasion	CD44-PI3K/AKT, VEGF/IL-8	Reprograms TME to suppress CD8+ T cell infiltration	αRANKL blockade, Anti-VEGF/IL-8 antibodies	NSCLC, bone metastatic cancers

OPN: Osteopontin; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; NEMO: NF-κB essential modulator; ATM: Ataxia-telangiectasia mutated; IKKα: IκB kinase alpha; HER2: Human epidermal growth factor receptor 2; EGFR: Epidermal growth factor receptor; EMT: Epithelial-mesenchymal transition; Bcl-2: B-cell lymphoma 2; DTL: Denticleless e3 ubiquitin protein ligase homolog; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B Cells; DRP1: Dynamin-related protein 1; LC3-II: Microtubule-associated protein 1A/1B-light chain 3-II; p62: Sequestosome 1; CD44: Cluster of differentiation 44; VEGF: Vascular endothelial growth factor; IL-8: Interleukin-8; PRDM15: PR/SET Domain 15; LY294002: PI3K inhibitors; αRANKL: Anti-receptor activator of nuclear factor kappa-B ligand antibody; VEGF: Vascular endothelial growth factor; GC: Gastric cancer; HCC: Hepatocellular carcinoma; NSCLC: Non-small cell lung cancer.

Table 4 Key mechanisms and interventions in targeted therapy of the Osteopontin-phosphatidylinositol 3-kinase/protein kinase B axis

Category	Key mechanisms	Intervention strategies	Related cancers
Small-molecule inhibitors	OPN activates PI3K/AKT to drive metastasis; PIK3CA mutations enhance pathway dependency	PI3Kα inhibitors (Alpelisib) combined with OPN-neutralizing antibodies	Pancreatic cancer, GC
Biomarker development	PIK3CA mutations (E542K/E545K) and OPN overexpression indicate PI3K activation; OPN regulates autophagy and immune microenvironment (IL-6/IL-8)	Alpelisib guided by PIK3CA mutation subtypes; Targeting OPN-immune interactions	GC, pancreatic cancer

OPN: Osteopontin; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; PIK3CA: Phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit alpha; E542K/E545K: Glutamic acid 542 to lysine/glutamic acid 545 to lysine; IL-6: Interleukin-6; IL-8: Interleukin-8; PI3Kα: Phosphatidylinositol 3-kinase catalytic subunit alpha; GC: Gastric Cancer.