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

Abstract

Background Currently, only trastuzumab, ramucirumab, and apatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease. Methods We investigated the immunohistochemical and fluorescence in situ hybridization expression of MET, ROS1, and ALK in four gastric cell lines and a cohort of 98 gastric cancer patients. Crizotinib response was studied in vitro and in vivo. Results Crizotinib potently inhibited in vitro cell growth in only one cell line, which also showed MET amplification. A positive correlation between crizotinib sensitivity and MET overexpression was observed (P = 0.045) in the histoculture drug response assay. Meanwhile, patientderived tumor xenograft mouse models transplanted with tissues with higher MET protein expression displayed a highly selective sensitivity to crizotinib. In the 98 patients, MET overexpression was found in 42 (42.9 %) and MET was amplified in 4 (4.1 %). ROS1 and ALK overexpression were found in 25 (25.5 %) and 0 patients, respectively. However, none of the patients screened harbored ALK or ROS1 rearrangements. No significant association was found between overall survival and MET or ROS1 status. We also observed a stage IV gastric cancer patient with MET amplification who experienced tumor shrinkage and clinical benefit after 3 weeks of crizotinib as fourth-line treatment. Conclusions Crizotinib may induce clinically relevant anticancer effects in MET-overexpressed or MET-amplified gastric cancer patients.

Analysis of the Effect of Increased α2,3-Sialylation on RTK Activation in MKN45 Gastric Cancer Spheroids Treated with Crizotinib

“…Crizotinib, a TKI for which we have shown promising in vitro results for the treatment of GC presenting MET amplification/overactivation, is already in clinical setting for the treatment of EML4-ALK-translocated (ALK-positive) non-small cell lung cancer (NSCLC) patients. In GC, 5% of patients present overactivation of the MET receptor and therefore, could benefit from crizotinib treatment, as also shown by others [45,46]. Our results show that increased α2,3-sialylation leads to reduced sensitivity to the TKI, including increased resistance to ALK inhibition.…”

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

“…The time to progression for these two patients receiving crizotinib treatment was approximately 112 and 105 days, respectively. A recent study also demonstrated the efficacy of crizotinib in a patient with stage IV gastric cancer positive for MET amplification (MET/CEP7 ratio of 2.0 or greater or 15 or more copies of genes in 10 % or more of tumor cells) [85]. Although crizotinib was administered as a fourth-line therapy in this patient, radiographic evidence of tumor shrinkage and symptomatic improvement were apparent after 3 weeks of treatment.…”

SwissMTB: establishing comprehensive molecular cancer diagnostics in Swiss clinics

“…For patient 11 we reported a significant MET overexpression with respect to the TCGA SKCM [ 37 ] cohort. In a recent study, Yang et al [ 79 ] reported tumor shrinkage and clinical benefit in gastric cancer patients with MET overexpression on crizotinib treatment. Based on these findings, off-label treatment with crizotinib was started.…”