Abstract C176: The combination of mTORC1/2 and PI3Kα inhibition alleviates PI3K pathway reactivation and leads to significant antitumor activity in multiple preclinical xenograft models.
Authors: Brake Rachael L. , Fabrey Robyn , Szwaya Jeff , Fitzgerald Michael , Iartchouk Natasha , Guo Xin , Kuida Keisuke , Zohren Fabian , Manfredi Mark 
Published: August 2014

Abstract
In many cancers, monotherapy targeted against signal transduction can lead to pathway reactivation by feedback mechanisms. The phosphoinositide 3-kinase (PI3K) pathway has been studied in this regard. Allosteric inhibitors of mammalian target of rapamycin complex 1 (mTORC1), such as rapamycin analogs, interrupt the normal negative regulation of insulin receptor substrate-1 (IRS-1) mediated by ribosomal protein S6 kinase (S6K), leading to pathway reactivation, as demonstrated by AKT phosphorylation and activation of its downstream substrates. Recent data suggest that administration of catalytic mTOR inhibitors can lead to similar feedback. Using in vitro models we have shown that the investigational catalytic mTORC1/2 inhibitor MLN0128 can lead to pathway reactivation, as measured by increases in AKT phosphorylation at threonine 308 (T308) over time. Furthermore we have shown pre-clinically that administration of the investigational isoform-selective PI3Kα inhibitor MLN1117 mitigates this pathway reactivation. In in vitro studies the combination of MLN0128 plus MLN1117 resulted in greater inhibition of key pathway regulators (pAKT, pS6, and p4EBP1) than either single agent alone, and a sustained decrease in AKT (T308) phosphorylation. The combination also induced greater apoptosis pre-clinically, as indicated by increases in cleaved poly (ADP-ribose) polymerase (PARP). The antiproliferative effects of this combination were assessed in 14 human tumor cell lines known to demonstrate sensitivity to single-agent MLN0128. In all settings (across tumor types and genotypes), administration of MLN0128 plus MLN1117 resulted in additive antiproliferative activity, except in two breast cancer models in which the activity of the combination was considered to show synergistic activity. In in vivo studies, concurrent oral administration of MLN0128 plus MLN1117 resulted in additive or synergistic antitumor activity in human tumor xenograft models. The combined antitumor activity correlated with modulation of pharmacodynamic markers and was observed irrespective of the dosing schedules tested or genotypes of the models, which included PI3K-mutant breast, PIK3CA/KRAS-mutant colon, PTEN-null breast, and EGFR-mutant non-small-cell lung cancer.The results from these preclinical experiments suggest that, in certain patient populations, co-administration of MLN0128 plus MLN1117 may lead to greater therapeutic effect than either single agent alone. The flexibility of being able to schedule these compounds independently and the isoform-selective profile of MLN1117 could provide distinct clinical advantages over other mechanisms of PI3K pathway inhibition. Together these data support the rationale that has led to the investigation of the safety of this combination clinically in an ongoing phase I study (NCT01899053).
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C176.
Citation Format: Rachael L. Brake, Robyn Fabrey, Jeff Szwaya, Michael Fitzgerald, Natasha Iartchouk, Xin Guo, Keisuke Kuida, Fabian Zohren, Mark Manfredi. The combination of mTORC1/2 and PI3Kα inhibition alleviates PI3K pathway reactivation and leads to significant antitumor activity in multiple preclinical xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C176.