STAT3 and ERK signaling are required for MET-addicted gastric cancer cell proliferation and survival.
Major finding: STAT3 and ERK signaling are required for MET-addicted gastric cancer cell proliferation and survival.
Concept: MET inhibition downregulates the ERK negative regulators DUSP4 and DUSP6, which leads to ERK reactivation.
Impact: Combined MEK and MET inhibition may combat MET inhibitor resistance in MET-amplified gastric cancer.
The gene encoding receptor tyrosine kinase MET is often amplified and activated in gastric cancer, but little is known about signaling downstream of MET prior to treatment with small-molecule MET inhibitors or upon acquired resistance. To further define the involvement of MET in gastric cancer, Lai and colleagues examined MET abundance in 35 primary and metastatic gastroesophageal junction adenocarcinomas. Strong MET staining positively correlated with proliferation markers and MET amplification. MET amplification was also found in gastric cancer cell lines with high MET protein expression and ligand-independent MET phosphorylation. Treatment of these cell lines with a small- molecule MET inhibitor resulted in the loss of MET phosphorylation and inhibition of anchorage-dependent and -independent growth, indicating that MET amplification confers dependence on MET activity. Temporal gene expression changes accompanied MET inhibition, including early transcription factor alterations and late reductions in cell cycle and DNA replication genes. Interestingly, differentially expressed genes largely overlapped with a STAT3 pathway signature, and STAT3 was rapidly dephosphorylated upon MET inhibition. Consistent with these findings, STAT3 inhibitors were as effective as MET inhibitors in reducing in vitro and in vivo MET-amplified gastric cancer cell line proliferation. In addition to a reduction in STAT3 activity, MET inhibition also reduced AKT and MEK–ERK signaling. However, ERK reactivation occurred in a subset of gastric cancer cell lines after prolonged MET inhibition due to downregulation of the ERK pathway negative regulators dual-specificity phosphatase 4 (DUSP4) 4 and DUSP6. Notably, a combined treatment with MET and MEK inhibitors significantly increased gastric cancer cell death in vitro compared with either agent alone. Taken together, these findings indicate that MET amplification induces several pro-proliferative signaling pathways in gastric cancer and a combination of MET and MAPK pathway inhibitors may be effective in combating resistance to MET inhibition in MET-addicted gastric cancers.