| Summary |
MET amplification is present in 20% of gastric cancers and has been confirmed as a therapeutic target in clinical trials. The molecular mechanisms of response and resistance to MET inhibitors are not well understood. We investigated the determinants of MET dependency in human gastric cancer. MET inhibition inhibited proliferation and induced cell death only in MET-amplified gastric cancer cell lines. The effects on growth arrest were stronger than the effects on cell death. To identify possible resistance mechanisms, we performed whole-genome mRNA expression profiling. Molecular changes related to autophagy were among the top alterations observed. Consistent with these findings, autophagy levels increased in a concentration-dependent manner when MET-amplified cells were exposed to crizotinib. Autophagy inhibition caused a dramatic decrease in apoptosis in one of the MET-amplified cell lines (MKN45) but not in the other (SNU-5). Because autophagy may provide energy in cells subjected to growth factor deprivation, we explored the effects of MET or autophagy inhibition on cellular ATP levels. This revealed that autophagy-dependent ATP production was selectively required for apoptosis in the MKN45 cells and that chemical ATP depletion mimicked the effects of autophagy inhibition to block cell death. Overall, the data reveal a novel relationship between ATP depletion and resistance to MET inhibitor-induced cell death. Our observations suggest that autophagy inhibitors could have unintended consequences when they are combined with growth factor receptor inhibitors in tumors that require autophagy-dependent ATP production for apoptosis. |
