Targets for Stomach Cancer

Understanding the molecular targets involved in stomach cancer pathogenesis is crucial for elucidating the mechanisms that drive tumor initiation, progression, metastasis, and treatment resistance. The targets identified here represent a spectrum of biological processes, including oncogenic signaling (ERBB2, FGFR2, RET, STAT3, MTOR), immune evasion (CD274/PD-L1, PDCD1/PD-1), cell adhesion and invasion (CLDN18, EPCAM), angiogenesis (KDR), drug resistance (ABCB1), and nucleotide metabolism (DPYD, TYMS, TOP1, TYMP, UMPS). Collectively, these targets reveal the complex interplay between genetic alterations, dysregulated signaling pathways, metabolic reprogramming, and the tumor microenvironment in stomach cancer. Their mechanistic roles not only inform the development of targeted therapies and immunotherapies but also provide robust biomarkers for patient stratification and prognosis. By focusing on targets with direct, evidence-based roles in gastric cancer, we enhance the precision of drug discovery and clinical intervention strategies.

Oncogenic Signaling And Growth Factor Receptors

This category includes targets that drive tumorigenesis and progression through aberrant activation of growth factor receptor signaling pathways and downstream effectors. These proteins are frequently amplified or mutated in stomach cancer, leading to uncontrolled proliferation, survival, and metastasis. The key targets are Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), Fibroblast Growth Factor Receptor 2 (FGFR2), Ret Proto-Oncogene (RET), Signal Transducer and Activator of Transcription 3 (STAT3), and Mechanistic Target of Rapamycin Kinase (MTOR).

Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)

ERBB2 encodes HER2, a transmembrane receptor tyrosine kinase with extracellular ligand-binding and intracellular kinase domains. Amplification or overexpression of ERBB2 occurs in 10-20% of gastric cancers, driving tumorigenesis via persistent activation of the PI3K/AKT and MAPK pathways. HER2 dimerizes with other EGFR family members, enhancing downstream signaling, cellular proliferation, and resistance to apoptosis. HER2 is a validated therapeutic target, with trastuzumab and other anti-HER2 agents improving outcomes in HER2-positive stomach cancer. HER2 status is a critical biomarker for patient selection. (Entrez: 2064, KEGG: 2064, UniProt: P04626)

Fibroblast Growth Factor Receptor 2 (FGFR2)

FGFR2 is a receptor tyrosine kinase with immunoglobulin-like extracellular domains and a cytoplasmic kinase domain. FGFR2 amplification or activating mutations are identified in up to 10% of gastric cancers, particularly the diffuse type. FGFR2 activation triggers MAPK, PI3K-AKT, and STAT pathways, promoting proliferation, survival, and angiogenesis. FGFR2-targeted therapies (e.g., bemarituzumab) are in clinical trials for FGFR2-altered gastric cancers. (Entrez: 2263, KEGG: 2263, UniProt: P21802)

Ret Proto-Oncogene (RET)

RET encodes a receptor tyrosine kinase with cadherin-like and cysteine-rich extracellular domains and a split kinase domain. RET fusions and overexpression have been reported in a subset of gastric cancers, especially those with a mesenchymal phenotype. RET activation stimulates RAS/MAPK and PI3K/AKT signaling, facilitating growth and metastasis. RET inhibitors (e.g., selpercatinib) are being explored for RET-driven tumors. (Entrez: 5979, KEGG: 5979, UniProt: P07949)

Signal Transducer and Activator of Transcription 3 (STAT3)

STAT3 is a transcription factor with SH2 and DNA-binding domains. Constitutive activation of STAT3, often via upstream cytokine/growth factor signaling (IL-6, EGFR, FGFR2), is observed in gastric cancer and correlates with poor prognosis. STAT3 promotes survival, immune evasion, angiogenesis, and epithelial-mesenchymal transition (EMT). Inhibitors of STAT3 are in preclinical development. (Entrez: 6774, KEGG: 6774, UniProt: P40763)

Mechanistic Target of Rapamycin Kinase (MTOR)

MTOR is a serine/threonine kinase with HEAT repeats and kinase domains, acting as a central regulator of cell growth, metabolism, and survival. MTOR is frequently activated in gastric cancer due to PI3K/AKT pathway alterations. Hyperactive mTOR signaling drives protein synthesis and tumor progression. mTOR inhibitors (e.g., everolimus) have shown limited but notable activity in gastric cancer clinical trials. (Entrez: 2475, KEGG: 2475, UniProt: P42345)

Immune Evasion And Checkpoint Regulation

This category includes targets that mediate immune escape by modulating immune checkpoints. Overexpression of these molecules enables tumor cells to evade immune surveillance, a key hallmark of stomach cancer, particularly in the context of high mutational burden and microsatellite instability. The principal targets are CD274 Molecule (PD-L1) and Programmed Cell Death 1 (PDCD1/PD-1).

CD274 Molecule (CD274)

CD274 encodes PD-L1, a transmembrane protein with IgV and IgC-like domains. PD-L1 is frequently upregulated in gastric cancer, especially in EBV-positive and MSI-high subtypes. PD-L1 binds PD-1 on T cells, inhibiting cytotoxic activity and promoting immune tolerance. PD-L1 expression is a predictive biomarker for immune checkpoint inhibitor therapy (e.g., pembrolizumab, nivolumab). (Entrez: 29126, KEGG: 29126, UniProt: Q9NZQ7)

Programmed Cell Death 1 (PDCD1)

PDCD1 encodes PD-1, an immunoglobulin superfamily receptor expressed on T cells. Upon engagement with PD-L1/PD-L2, PD-1 transduces inhibitory signals via its ITIM/ITSM motifs, reducing T cell activation. PD-1 pathway upregulation is a central mechanism of immune escape in gastric cancer. PD-1 inhibitors are approved for advanced or MSI-high gastric cancer. (Entrez: 5133, KEGG: 5133, UniProt: Q15116)

Cell Adhesion, Invasion, And Metastasis

This category encompasses targets that regulate cell-cell adhesion, epithelial integrity, and invasive behavior. Loss or alteration of these molecules contributes to tumor dissemination and poor prognosis in stomach cancer. Relevant targets include Claudin 18 (CLDN18) and Epithelial Cell Adhesion Molecule (EPCAM).

Claudin 18 (CLDN18)

CLDN18 encodes a tight junction protein with four transmembrane domains. CLDN18.2 isoform is selectively expressed in gastric mucosa and retained in some gastric cancers. Loss or aberrant expression of CLDN18 disrupts epithelial barrier function, facilitating invasion and metastasis. CLDN18.2 is a target for monoclonal antibody therapy (e.g., zolbetuximab) in clinical trials. (Entrez: 51208, KEGG: 51208, UniProt: P56856)

Epithelial Cell Adhesion Molecule (EPCAM)

EPCAM is a transmembrane glycoprotein with an extracellular EGF-like domain. EPCAM is overexpressed in gastric cancer, promoting proliferation, migration, and stemness. It disrupts cell-cell adhesion and is associated with poor prognosis. EPCAM is a diagnostic and therapeutic target, with antibody-drug conjugates in development. (Entrez: 4072, KEGG: 4072, UniProt: P16422)

Angiogenesis And Tumor Vascularization

This category includes targets that regulate angiogenesis, supporting tumor growth and metastasis by promoting new blood vessel formation. Kinase Insert Domain Receptor (KDR/VEGFR2) is the principal mediator of VEGF-driven angiogenesis in gastric cancer.

Kinase Insert Domain Receptor (KDR)

KDR encodes VEGFR2, a receptor tyrosine kinase with seven immunoglobulin-like extracellular domains and a split kinase domain. VEGFR2 is highly expressed in gastric cancer vasculature. VEGF-A/VEGFR2 signaling drives angiogenesis, facilitating tumor growth and metastasis. Anti-angiogenic therapies (ramucirumab, apatinib) target this axis and are approved for advanced gastric cancer. (Entrez: 3791, KEGG: 3791, UniProt: P35968)

Chemoresistance And Drug Efflux

This category comprises targets that mediate resistance to chemotherapy by actively exporting drugs from tumor cells. ATP Binding Cassette Subfamily B Member 1 (ABCB1) is a key efflux transporter implicated in multidrug resistance in stomach cancer.

ATP Binding Cassette Subfamily B Member 1 (ABCB1)

ABCB1 encodes P-glycoprotein, an ATP-dependent transmembrane efflux pump with two nucleotide-binding domains and two transmembrane domains. Overexpression of ABCB1 in gastric cancer leads to efflux of cytotoxic drugs (e.g., paclitaxel, doxorubicin), conferring multidrug resistance. Inhibitors of ABCB1 are under investigation to overcome chemoresistance. (Entrez: 5243, KEGG: 5243, UniProt: P08183)

Nucleotide Metabolism And Dna Synthesis

This category includes enzymes involved in nucleotide metabolism and DNA synthesis, which are critical for tumor cell proliferation and serve as targets for cytotoxic chemotherapy. Key targets are Dihydropyrimidine Dehydrogenase (DPYD), DNA Topoisomerase I (TOP1), Thymidine Phosphorylase (TYMP), Thymidylate Synthetase (TYMS), and Uridine Monophosphate Synthetase (UMPS).

Dihydropyrimidine Dehydrogenase (DPYD)

DPYD is a cytosolic enzyme with FMN, FAD, and iron-sulfur binding domains, catalyzing the rate-limiting step in 5-fluorouracil (5-FU) catabolism. DPYD deficiency leads to severe 5-FU toxicity. DPYD expression and polymorphisms are predictive biomarkers for 5-FU-based chemotherapy safety and efficacy in gastric cancer. (Entrez: 1806, KEGG: 1806, UniProt: Q12882)

DNA Topoisomerase I (TOP1)

TOP1 is a nuclear enzyme with a core catalytic domain that relaxes supercoiled DNA during replication and transcription. TOP1 is a target of camptothecin derivatives (e.g., irinotecan), which are used in gastric cancer chemotherapy. Overexpression or mutation of TOP1 may influence drug response. (Entrez: 7150, KEGG: 7150, UniProt: P11387)

Thymidine Phosphorylase (TYMP)

TYMP is a cytosolic enzyme with a phosphorylase domain, catalyzing thymidine catabolism. TYMP is upregulated in gastric cancer and promotes angiogenesis and tumor progression. It is also involved in the activation of fluoropyrimidine prodrugs (e.g., capecitabine). High TYMP expression correlates with poor prognosis and altered drug response. (Entrez: 1890, KEGG: 1890, UniProt: P19971)

Thymidylate Synthetase (TYMS)

TYMS is a folate-dependent enzyme with a catalytic domain, essential for de novo dTMP synthesis. TYMS is the main target of 5-FU and related drugs. Overexpression of TYMS confers resistance to 5-FU and is associated with poor outcomes in gastric cancer. (Entrez: 7298, KEGG: 7298, UniProt: P04818)

Uridine Monophosphate Synthetase (UMPS)

UMPS is a bifunctional enzyme with orotate phosphoribosyltransferase and orotidine-5'-phosphate decarboxylase domains, catalyzing pyrimidine biosynthesis. UMPS expression modulates sensitivity to fluoropyrimidines in gastric cancer. (Entrez: 7372, KEGG: 7372, UniProt: P11172)