MET, FOXM1 and DNA damage-induced senescence

Purpose: Deregulated signaling via the MET receptor tyrosine kinase is abundant in gastric tumors, with up to 80% of cases displaying aberrant MET expression. A growing body of evidence suggests MET as a potential target for tumor radiosensitization. Experimental Design: Cellular proliferation and DNA damage-induced senescence were studied in a panel of MET-overexpressing human gastric cancer cell lines as well as in xenograft models following MET inhibition and/or ionizing radiation. Pathways activation and protein expression were assessed by immunoblotting and immunohistochemistry. Tumor tissue microarrays (91 gastric cancer patients) were generated and copy number alteration (178 patients) and gene expression (373 patients) data available at The Cancer Genome Atlas were analyzed to assess co-alterations of MET and FOXM1. Results: MET targeting administered prior ionizing radiation instigates DNA damage-induced senescence (~80%, P<0.001) rather than cell death. MET inhibition-associated senescence is linked to blockade of the MAPK pathway, correlates with downregulation of FOXM1 and can be abrogated (11,8% vs. 95,3%, P<0.001) by ectopic expression of FOXM1 in the corresponding gastric tumor cells. Cells with ectopic FOXM1 expression demonstrate considerable (~20%, P<0.001) growth advantage despite MET targeting, suggesting a novel clinically-relevant resistance mechanism to MET inhibition as the co-presence of both MET and FOXM1 protein (33%) and mRNA (30%) overexpression as well as gene amplification (24,7%) is common in patients with gastric cancer. Conclusions: FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors.

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