Published online May 21, 2016. doi: 10.3748/wjg.v22.i19.4638
Peer-review started: January 11, 2016
First decision: March 21, 2016
Revised: April 1, 2016
Accepted: April 20, 2016
Article in press: April 20, 2016
Published online: May 21, 2016
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.
Core tip: Among various cellular signaling pathways, hepatocyte growth factor/c-MET, phosphoinositide 3-kinase/Akt/mammalian target of rapamycin and janus kinase 2/signal transducer and activator of transcription 3 pathways are reportedly important in gastric carcinogenesis and metastasis. Aberrations of immune checkpoints have been vigorously investigated. However, clinical results of their target agents have not always matched the theoretical expectations of efficacy. In this review, we summarize the biologic impacts of the aforementioned signaling pathways, and their recent clinical outcomes including those of multiple kinase inhibitors in gastric cancer.