In vitro
AMG 458 can potently inhibit human c-Met and mouse c-Met with Ki of 1.2 nM or 2.0 nM. AMG-458 enhances radiosensitivity in H441 but not in A549. A549 expresses low levels of c-Met, which were phosphorylated only in the presence of exogenous hepatocyte growth factor. The combination of radiation therapy and AMG-458 treatment synergistically increase apoptosis in the H441 cell line but not in A549. Radiation therapy, AMG-458, and combination treatment were found to reduce p-Akt and p-Erk levels in H441 but not in A549. H441 became less sensitive to AMG-458 after small interfering RNA knockdown of c-Met; there was no change in A549. After overexpression of c-Met, A549 became more sensitive, while H441 became less sensitive to AMG-458. AMG-458 is more effective in cells that expressed higher levels of c-Met/p-Met.
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