Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy

Hans-Guido Wendel, Elisa de Stanchina, Jordan S. Fridman, Abba Malina, Sagarika Ray, Scott Kogan, Carlos Cordon-Cardo, Jerry Pelletier and Scott W. Lowe ()
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Hans-Guido Wendel: Cold Spring Harbor Laboratory
Elisa de Stanchina: Cold Spring Harbor Laboratory
Jordan S. Fridman: Cold Spring Harbor Laboratory
Abba Malina: McGill University
Sagarika Ray: Cold Spring Harbor Laboratory
Scott Kogan: University of California-San Francisco
Carlos Cordon-Cardo: Memorial Sloan-Kettering Cancer Center
Jerry Pelletier: McGill University
Scott W. Lowe: Cold Spring Harbor Laboratory

Nature, 2004, vol. 428, issue 6980, 332-337

Abstract: Abstract Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis1. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance2. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro3. 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.

Date: 2004
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DOI: 10.1038/nature02369

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