TRANSLATIONAL IMPACT

Abstract

Most human cancers possess mutations in genes that lead to hyperactivation of the Akt signalling pathway, which promotes cellular growth and proliferation, such as the lipid phosphatase PTEN. Studies of various animal models have shown that knocking out components of the Akt signalling pathway suppresses tumorigenesis in the context of PTEN loss or other cancer-causing mutations that activate the Akt pathway. These exciting results have stimulated pharmaceutical companies to develop small-molecule inhibitors that suppress the Akt pathway as anticancer agents. However, treatment of patients with drugs that target the Akt pathway at well-tolerated doses will only partially reduce Akt activity and not ablate it, as in experimental mouse knockout models. It is therefore unclear how relevant previous studies using mouse knockout models are in validating the efficacy of Akt-pathway inhibitors as anticancer agents.In this paper, the authors define the effect of a moderate ∼twofold inhibition of Akt activity on the initiation and growth of PTEN-deficient tumours. The mouse model they developed carries a mutation in the PH domain of PDK1 that prevents an interaction between PDK1 and the PtdIns(3,4,5)P3 second messenger, thereby reducing the activation of all Akt isoforms in vivo. The authors argue that, compared with previous knockout mouse models, in which Akt activity is completely ablated, the partial inhibition of Akt in the PDK1-PH domain mutant mouse more accurately mimics the effect observed in a cancer patient treated with an Akt inhibitor. The authors demonstrate that introducing the PDK1-PH domain mutation into PTEN+/− mice reduced the activity of Akt isoforms ∼twofold and markedly delayed the development of a wide range of spontaneous tumours by ∼4 months. Moreover, the PDK1-PH domain mutation markedly slowed the growth of B-cell follicular lymphomas that developed in PTEN+/− mice. These data emphasise the dependence of PTEN-deficient tumours on intrinsic Akt kinase activity and suggest that even moderate reduction in this activity can significantly delay tumour initiation and development.This study will provide encouragement to pharmaceutical companies that are currently elaborating Akt-pathway inhibitors, because it suggests that even agents that modestly reduce Akt activation might have significant therapeutic benefit on a broad range of common human tumours. It also suggests that drugs that inhibit the binding of PDK1 to PtdIns(3,4,5)P3 could be developed for use either alone or in combination with other Akt-pathway suppressors to treat cancer. Further work is required to establish the key downstream pathways by which Akt mediates effects on tumour initiation and development observed in this study.