1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
2. McGill University, Montreal, H3G1Y6, Quebec, Canada
3. University of California-San Francisco, San Francisco, California 94143-0128, USA
4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
5. Present address: Incyte Corporation, Wilmington, Delaware 19880, USA

Correspondence to: Scott W. Lowe¹ Email: lowe@cshl.edu

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.

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