Abstract 3855: Investigation of the growth inhibitory activity of the MEK inhibitor ARRY-438162 in combination with everolimus in a variety of KRas and PI3K pathway mutant cancers

The RAS/RAF/MEK/ERK and PI3K signaling pathways are known to play key roles in cell growth, proliferation and survival. Targeted agents against factors in these pathways have been shown to provide therapeutic benefit in the treatment of cancer. However, there exists a considerable degree of cross-talk between these pathways such that when one pathway is inhibited the other is upregulated to sustain growth and survival signaling. Therefore, it would be expected that the concomitant use of targeted agents against both of these pathways would overcome the negative effects of this crosstalk, and enhance the ability of these agents to block cancer cell growth. We sought to understand whether or not the combination of the MEK inhibitor ARRY-438162 and the TORC1 inhibitor Everolimus would combine to enhance cell killing compared to the activity of the single agents. It has been established that in the majority of cancers, constituents of one or both of these pathways are mutated conferring constitutive activation to the pathway. Thus, we investigated whether key common mutations in either of these pathways conferred particular sensitivity or resistance to the combination. The growth inhibitory activities of ARRY-438162 and Everolimus were assessed alone and in combination in 26 different cell lines from a variety of human cancers with documented mutations in the KRAS, PTEN, PI3K and BRAF genes. In this regard, we report the identification of key genotypes that are associated with antagonistic, additive, and synergistic responses to the combination. In particular, treatment of the NCI-H460 NSCLC line [KRASG12D/PIK3CA] was only modestly responsive to either ARRY-162 or Everolimus as single agents (10% and 20% growth inhibition, respectively). However, the combination significantly inhibited the growth of this line, a result that was confirmed as synergistic by Bliss analysis. In order to validate the relevance of our in vitro data, an in vivo study was performed using NCI-H460 xenografts in nude mice. Everolimus alone showed no tumor growth inhibition while ARRY-438162 at doses of 30, 100 and 300 mg/kg, BID produced dose-related modest tumor growth inhibition (up to ∼50%). Combining the agents produced enhanced activity at all dose levels of ARRY-438162 without altering the exposure of either agent. Finally, in addition to growth inhibition, the biochemical effects of the single agent and the combination treatment on S6 protein, Erk, Akt, and various apoptosis regulator proteins were assessed as well as their effects on apoptosis and autophagy. ARRY-438162 having demonstrated significant tumor growth inhibitory activity in numerous pre-clinical models and acceptable preclinical and clinical safety profiles has advanced into Phase 1 clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3855.