Abstract B20: In vitro and in vivo antitumor activities of the dual PI3K/mTor inhibitor NVP‐BEZ235. Implications for patient stratification strategies

The abnormal activation of the PI3K pathway is a recurrent feature observed in human tumors. Epidemiological and experimental studies have clearly underlined the role of this pathway for the maintenance of the tumorigenic state. A number of the intracellular components of this pathway have been targeted as anticancer drug discovery activities leading to clinical candidates like NVP‐BEZ235. This compound, which is a dual pan‐PI3K/mTOR, is currently undergoing Phase I clinical trials.To identify cancer patient populations that would benefit from NVP‐BEZ235 treatment, the compound was profiled pre‐clinically in a panoply of tumor cell lines, either in vitro or in vivo settings. Although not predictive from the in vitro antiproliferative data, the observed in vivo antitumor effects could be classified in three groups: strong, medium and low responders. Interestingly, 2 out of the 4 strong tumor xenograft responders presented genetic alterations of EGFR members. Constitutively active mutants or amplification of EGFR members is frequently observed in breast, ovarian and in non small cell lung cancer. Follow‐up in vitro studies using a panel of over 40 breast cancer cell lines showed that a better understanding of tumor cell sensitivity to BEZ235 treatment could be obtained when cell death was used as a readout. ErbB2 amplification and/or PIK3CA activating mutations correlated well with cell death induction, but not PTEN deletion or mutations. An in depth analysis of death markers revealed that the cell death observed with BEZ235 could be recapitulated with other PI3K inhibitors and that this event is linked with active PARP cleavage reflective of an apoptotic process. Moreover, the effect seemed to be independent of Caspase‐9 executioner and mitochondrial activated caspase, suggesting an alternate route for apoptosis induction by this class of compound. The exact mechanism is currently being elucidated. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer Phase II trials for BEZ235 Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B20.