MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Gastric cancer treatment options are limited, with only trastuzumab, ramucirumab, and apatinib showing efficacy.
• Novel therapeutic targets are urgently needed for effective gastric cancer management.

Purpose of the Study:

• To investigate the potential of crizotinib as a targeted therapy for gastric cancer.
• To evaluate the expression of MET, ROS1, and ALK in gastric cancer cell lines and patient cohorts.
• To correlate crizotinib sensitivity with the expression levels of these biomarkers.

Main Methods:

• Immunohistochemistry and fluorescence in situ hybridization were used to assess MET, ROS1, and ALK expression in four gastric cell lines and 98 gastric cancer patients.
• In vitro and in vivo studies were conducted to determine crizotinib's efficacy.
• Correlation analysis was performed to link biomarker expression with treatment response.

Main Results:

• Crizotinib demonstrated potent in vitro inhibition of cell growth in a cell line with MET amplification.
• A significant positive correlation was observed between crizotinib sensitivity and MET overexpression (P=0.045).
• Patient-derived tumor xenografts with higher MET expression showed selective sensitivity to crizotinib. MET overexpression was found in 42.9% and amplification in 4.1% of patients; ROS1 in 25.5%, ALK in 0%.
• A patient with stage IV gastric cancer and MET amplification experienced tumor shrinkage with crizotinib treatment.

Conclusions:

• Crizotinib exhibits potential anticancer effects in gastric cancer patients with MET overexpression or amplification.
• MET status may serve as a predictive biomarker for crizotinib therapy in gastric cancer.
• Further clinical investigation is warranted to establish crizotinib's role in gastric cancer treatment.