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. 2004 Mar 18;428(6980):332-7.
doi: 10.1038/nature02369.

Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy

Hans-Guido Wendel  1 , Elisa De Stanchina, Jordan S Fridman, Abba Malina, Sagarika Ray, Scott Kogan, Carlos Cordon-Cardo, Jerry Pelletier, Scott W Lowe
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Free article

Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy

Hans-Guido Wendel et al. Nature. .
Free article

Abstract

Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.

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