Advancing human epidermal growth factor receptor 2-positive gastric cancer therapy: Toward targeted immunotherapy and antibody-drug conjugates

Table 4 Overview of resistance mechanisms to human epidermal growth factor receptor 2-targeted therapy and corresponding strategies

Resistance mechanism	Key molecular events and evidence	Consequences	Potential overcoming strategies	Ref.
HER2 gene mutations and structural alterations	Antibody-mediated drug resistance. L755S mutation: Mediates acquired resistance to TKIs. p95HER2 truncation: Lacks the extracellular domain, evading trastuzumab binding while constitutively activating downstream signaling. Splicing mutation (c.1899-1G>A): Leads to exon skipping, altering the HER2 protein structure	Reduced antigen expression, antigen masking, antigen truncation, target mutations, and antigen internalization. Markedly reduced drug-binding affinity. Sustained activation of downstream oncogenic signaling. Therapeutic escape facilitated by intratumoral heterogeneity	Switch to agents with distinct mechanisms (e.g., ADCs). Implement dual HER2 blockade (e.g., trastuzumab + pertuzumab). Employ NGS to guide therapy selection	Schiff et al[96]; Chen et al[97]; O'keefe et al[98]; Jebbink et al[99]; Jiao et al[100]; Marchiò et al[101]; Sperinde et al[102]; Goh et al[103]; Janiszewska et al[104]
Aberrant downstream pathway activation	PIK3CA H1047R mutation: Sustains PI3K/AKT/mTOR signaling despite HER2 blockade. PTEN loss: Leads to constitutive PI3K pathway activation. NF1 loss/KRAS mutation: Activates the RAS/MAPK pathway, driving resistance via the MEK-CDK2 axis	Bypasses upstream HER2 inhibition, maintaining survival and proliferation signals. Alters oncogenic dependency, driving cell cycle progression	Combine PI3K/mTOR inhibitors (e.g., alpelisib). Combine MEK inhibitors (e.g., trametinib). Combine CDK4/6 or explore CDK2 inhibitors	Schiff et al[96]; Janiszewska et al[104]; Smith and Chandarlapaty[105]; Yu et al[106]; Garay et al[107]; Garay et al[108]; Smith et al[109]
Cell survival related mechanisms	AKT-mediated phosphorylation: Inhibits pro-apoptotic proteins (e.g., BAD, caspase-9), blocking mitochondrial apoptosis (cytochrome c release). AKT/mTOR signaling: Promotes G1/S transition by regulating cyclin D1/CDKs and downregulating p27Kip1	Induces an “apoptosis-resistant” phenotype, elevating cell survival threshold. Disrupts cell cycle checkpoints, enabling continuous proliferation (reflected by elevated Ki-67)	Target persistent downstream survival signals (e.g., with AKT inhibitors). Exploit cell cycle vulnerabilities (e.g., with CDK inhibitors)	Smyth et al[3]; Bang et al[8]; Gravalos and Jimeno[9]; Friedlaender et al[22]; Sareyeldin et al[23]; Dumitru et al[24]; Jensen et al[25]; Wang et al[110]; Bassi et al[111]
Bypass signaling activation	MET amplification/overexpression: Provides potent alternative survival signaling. FGFR pathway activation: Suppresses apoptosis and induces angiogenesis and EMT. AXL upregulation: Induced by hypoxia, promotes EMT and immune resistance. ER-HER2 crosstalk: Mediates cross-resistance via the CDK4/6-Rb axis	Establishes independent signaling circuits for proliferation and survival. Fuels malignant progression and facilitates immune evasion	Co-administer MET, FGFR, or AXL inhibitors. For HR+ patients, combine CDK4/6 inhibitors with endocrine therapy. Modulate the TME (e.g., alleviate hypoxia)	Pernas and Tolaney[35]; Schiff et al[96]; Szymczyk et al[112]; Wang et al[113]; Recondo et al[114]; Mami-Chouaib et al[115]; Koirala et al[116]; Mahdi et al[117]; Shagisultanova et al[118]; Clark et al[119]
Tumor heterogeneity	Spatial heterogeneity: Non-uniform HER2 expression within a tumor, risking sampling error in biopsies. Temporal heterogeneity: Clonal evolution under therapeutic pressure selects for resistant subpopulations	Inherent treatment failure due to untargeted cell populations. Leads to acquired resistance and disease relapse	Perform multi-region biopsy for accurate assessment. Utilize liquid biopsy for dynamic monitoring. Initiate potent combination regimens (e.g., dual HER2 blockade)	Schiff et al[96]; Wang et al[113]; Suenaga et al[120]
Tumor microenvironment remodeling	Metabolic reprogramming: Enhanced glycine/serine metabolism supports one-carbon units and nucleotide synthesis. Immunosuppression: Dysfunctional TILs and upregulated immune checkpoints. ECM remodeling: Integrin-mediated pro-survival signaling	Provides biosynthetic precursors and energy for tumor growth. Creates a physical and immunosuppressive barrier against therapy	Target key metabolic enzymes. Combine immune checkpoint inhibitors. Develop novel strategies targeting the ECM	Schiff et al[96]; Abuelreich et al[121]

HER2: Human epidermal growth factor receptor 2; TKI: Tyrosine kinase inhibitor; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; MAPK: Mitogen-activated protein kinase; MEK: Mitogen-activated protein kinase kinase; CDK: Cyclin-dependent kinase; MET: Mesenchymal-epithelial transition factor; FGFR: Fibroblast growth factor receptor; EMT: Epithelial-mesenchymal transition; ER: Estrogen receptor; TIL: Tumor-infiltrating lymphocyte; ECM: Extracellular matrix; NGS: Next-generation sequencing; ADC: Antibody-drug conjugate; HR: Hormone receptor; TME: Tumor microenvironment.