Oncogenic shock: turning an activated kinase against the tumor cell.
Accumulating evidence indicates that mutationally activated kinases are especially good targets for anti-cancer drugs. It has been suggested that this reflects a state of "oncogene addiction" of tumor cells. We recently reported experimental studies that may provide a molecular mechanism to explain such apparent dependency. We find that oncogenic kinases produce both pro-survival and pro-apoptotic signals that decay at different rates upon oncogene inactivation. Pro-survival signals are rapidly attenuated, whereas pro-apoptotic signals are relatively longer-lived. This differential signal decay creates a temporal window during which pro-apoptotic outputs from the oncogenic kinase predominate to actively promote tumor cell death upon kinase inhibition. We refer to this mechanism as "oncogenic shock", and suggest that it has significant implications for the optimal therapeutic use of targeted kinase inhibitors.
Sharma
Sreenath V
SV
Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Settleman
Jeffrey
J
D000818:Animals; D017209:Apoptosis; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology*; D011494:Protein Kinases / Q000378:metabolism*
D011494:Protein Kinases