Advances and challenges in gastric cancer testing: the role of biomarkers

Key molecular alterations and signaling pathways involved in the pathogenesis and progression of gastric cancer, along with selected targeted therapies (adapted from Lei et al.⁸). Many biomarkers have been associated with gastric cancer, such as molecules in growth factors pathways and immune checkpoint control modulators. Growth factor receptors (e.g., HER2, MET, and FGFR2) typically activate essential downstream pathways through dimerization and tyrosine kinase signaling. The downstream pathways, including PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, and JAK/STAT/IRF, mediate essential cellular processes, including growth, proliferation, differentiation and survival, and participate in the tumorigenesis and progression of many cancer types. DKK1 regulates the Wnt/β-catenin signaling pathway, which is also an essential pathway involved in cell proliferation, migration, and death. PD-L1 binds to PD-1 and suppresses T-cell receptor signaling, and this mechanism is commonly hijacked by cancer cells to escape immune recognition. On a related note, dysregulated expression of the MMR genes can impair cellular repair function during DNA replication, resulting in the MSI-H/dMMR phenotype. This phenotype contributes to gastric cancer through different mechanisms, including an upregulated PD-L1 expression. Likewise, EBV is associated with different oncogenic effects and it is known to increase PD-L1 expression through the JAK/STAT/IRF pathway. B7-H3 and VISTA are also immune checkpoint proteins and have been associated with immune invasion in gastric cancer. Another notable biomarker is CLDN18.2, a tight junction protein commonly expressed in differentiated gastric mucosa cells. CLDN18.2 may become more exposed when tight junctions are disrupted upon malignant transformation of gastric epithelial cells. In terms of biomarker-guided treatments for gastric cancer, trastuzumab and trastuzumab deruxtecan are recommended for patients with HER2-positivity. PD-L1-positivity and MSI-H/dMMR can guide the use of immunotherapies, such as pembrolizumab. Zolbetuximab has been approved for patients with CLDN18.2-positive disease in some countries. More targeted therapies, including savolitinib for MET-positive patients, are currently under clinical investigation. AKT, protein kinase B; APC, adenomatous polyposis coli; CLDN18.2, claudin 18.2; CKIα, casein kinase Iα; DKN-01, Dikkopf-1 monoclonal antibody 1; DKK1, Dikkopf-1; DVL, disheveled; EBV, Epstein-Bar virus; EBNA, Epstein-Bar nuclear antigen; ERK1/2, extracellular signal-regulated kinase 1/2; FGFR2, fibroblast growth factor receptor 2; HER2, human epidermal growth factor receptor 2; GSK-3β, glycogen synthase kinase 3β; IFH, interferon; IRF, interferon regulatory factor; JAK, Janus kinase; LRP5/6, low-density lipoprotein receptor-related protein 5/6; MEK1/2, mitogen-activated protein kinase 1/2; MSI-H/dMMR, microsatellite instability high/defective mismatch repair; mTOR, mammalian target of rapamycin; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PDK1, phosphoinositide-dependent protein kinase 1; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol diphosphate; PIP3, phosphatidylinositol 3-phosphate; PTEN, phosphatase and tensin homolog; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; STAT, signaling transducer and activator of transcription; TCF/LEF T-cell factor/lymphoid enhancer factor; TSC1/2, tuberous sclerosis complex 1/2; VISTA, V-domain immunoglobulin-containing suppressor of T-cell activation.