TY - JOUR
T1 - "Oncogenic shock"
T2 - Explaining oncogene addiction through differential signal attenuation
AU - Sharma, Sreenath V.
AU - Fischbach, Michael A.
AU - Haber, Daniel A.
AU - Settleman, Jeffrey
AU - Eisen, Tim
AU - Johnson, Bruce
AU - Johnson, David
PY - 2006/7/15
Y1 - 2006/7/15
N2 - "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.
AB - "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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U2 - 10.1158/1078-0432.CCR-06-0096
DO - 10.1158/1078-0432.CCR-06-0096
M3 - Article
C2 - 16857816
AN - SCOPUS:33746388176
SN - 1078-0432
VL - 12
SP - 4392s-4395s
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -