title: Recent updates of precision therapy for gastric cancer: Towards optimal tailored management.
abstract: Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among them, hepatocyte growth factor (HGF)/c-MET, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. Recently, aberrations of immune checkpoints including programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of novel agents targeting these signaling pathways. However, phase III studies of selective anti-HGF/c-MET antibodies and mTOR inhibitor failed to show significant benefits in terms of overall survival and progression-free survival. Few agents directly targeting STAT3 have been developed. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link to effectively inhibit STAT3 activity. Inhibition of PD-1/PD-L1 showed durable efficacy in phase I studies, and phase III evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to identify good responders. Regorafenib has shown promising effectiveness in prolonging progression-free survival in a phase II study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways.
authors.affiliation: Moon Kyung Joo, Jong-Jae Park, Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, Seoul 08308, South Korea.
authors.forename: Moon Kyung
authors.initials: MK
authors.lastname: Joo
authors.affiliation: Moon Kyung Joo, Jong-Jae Park, Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, Seoul 08308, South Korea.
authors.forename: Jong-Jae
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Moon Kyung Joo, Jong-Jae Park, Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, Seoul 08308, South Korea.
authors.forename: Hoon Jai
authors.initials: HJ
authors.lastname: Chun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D020022:Genetic Predisposition to Disease; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D018579:Patient Selection; D010641:Phenotype; D011110:Polymorphism, Genetic; D057285:Precision Medicine / Q000379:methods*; D011237:Predictive Value of Tests; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: Gastric cancer; Hepatocyte growth factor; Mammalian target of rapamycin; Programmed cell death ligand-1; Signal transducer and activator of transcription 3