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"Oncogenic Shock": Explaining Oncogene Addiction through Differential Signal Attenuation

Authors' Affiliation: Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Jeffrey Settleman, Center for Molecular Therapeutics, MGH Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129. Phone: 617-724-9556; E-mail: settleman{at}helix.mgh.harvard.edu.

"Oncogene addiction" describes the curious acquired dependence of tumor cells on an activated oncogene for their survival and/or proliferation, a phenomenon that has important implications for the success of targeted cancer therapies. However, the mechanisms explaining oncogene addiction remain elusive. We propose that "addiction" may be an illusion generated as a consequence of differential attenuation rates of prosurvival and proapoptotic signals emanating from an oncoprotein acutely following its inactivation. According to this model, which we call "oncogenic shock," prosurvival signals dissipate quickly on oncoprotein inactivation whereas proapoptotic signals linger sufficiently long to commit the cell to an apoptotic death. This mechanism may contribute to the rapid and dramatic clinical responses observed in some cancer patients treated with selective tyrosine kinase inhibitors and could yield additional drug targets that determine the balance of signaling outputs from activated oncoproteins.

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