"Oncogenic shock": Explaining oncogene addiction through differential signal attenuation

Sreenath V. Sharma, Michael A. Fischbach, Daniel A. Haber, Jeffrey Settleman, Tim Eisen, Bruce Johnson, David Johnson

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

"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.

Original languageEnglish (US)
JournalClinical Cancer Research
Volume12
Issue number14
DOIs
StatePublished - Jul 15 2006

Fingerprint

Oncogene Proteins
Oncogenes
Shock
Neoplasms
Protein-Tyrosine Kinases
Survival
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

"Oncogenic shock" : Explaining oncogene addiction through differential signal attenuation. / Sharma, Sreenath V.; Fischbach, Michael A.; Haber, Daniel A.; Settleman, Jeffrey; Eisen, Tim; Johnson, Bruce; Johnson, David.

In: Clinical Cancer Research, Vol. 12, No. 14, 15.07.2006.

Research output: Contribution to journalArticle

Sharma, Sreenath V. ; Fischbach, Michael A. ; Haber, Daniel A. ; Settleman, Jeffrey ; Eisen, Tim ; Johnson, Bruce ; Johnson, David. / "Oncogenic shock" : Explaining oncogene addiction through differential signal attenuation. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 14.
@article{83900192516f43c8a72e4edd88adb05f,
title = "{"}Oncogenic shock{"}: Explaining oncogene addiction through differential signal attenuation",
abstract = "{"}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.",
author = "Sharma, {Sreenath V.} and Fischbach, {Michael A.} and Haber, {Daniel A.} and Jeffrey Settleman and Tim Eisen and Bruce Johnson and David Johnson",
year = "2006",
month = "7",
day = "15",
doi = "10.1158/1078-0432.CCR-06-0096",
language = "English (US)",
volume = "12",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=33746388176&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746388176&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-06-0096

DO - 10.1158/1078-0432.CCR-06-0096

M3 - Article

C2 - 16857816

AN - SCOPUS:33746388176

VL - 12

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 14

ER -