Abstract 4491: Novel multiplex PI3-kinase inhibitors potently inhibit Ras-mutated tumors via suppression of eIF-4E-mediated protein translation

Abstract

Abstract Background: The PI3K pathway is a target of significant interest for cancer drug development due to its prominent role in cancer cell growth and survival. However, PI3K pathway inhibition alone has limited efficacy in the presence of oncogenic Ras mutations, which are found in approximately one-third of all human tumors. In preclinical models, efficacy in Ras-mutated tumors has required the inhibition of both PI3K and other Ras-activated pathways. One key function of these pathways is to regulate eIF-4E, a central factor in cap-dependent translation of critical proteins involved in growth and survival (e.g., c-myc and Mcl-1), and anti-tumor activity has been associated with the selective inhibition of translation of these proteins. Simultaneous inhibition of PI3K and other Ras-activated pathways that converge on eIF-4E-mediated protein translation represents an attractive strategy for oncology drug development. Methods and Results: Using rational drug design, we identified a novel chemical series of small molecules that possess potent activity against PI3K and additional Ras-regulated kinases implicated in protein translation. The anti-tumor activity of these multiplex PI3K inhibitors was assessed against a panel of 30 human tumor cell lines comprised of various genetic backgrounds and histotypes. Multiplex PI3K inhibitors demonstrated broad and potent anti-proliferative activity in all cell lines tested (EC50: 10 nM - 500 nM) and induced cell death in Ras-mutated cell lines (e.g., PANC-1, HCT116 and A549). Mechanistically, these multiplex PI3K inhibitors induced caspase activity, inhibited the phosphorylation of AKT, 4E-BP1, ribosomal S6 and eIF-4E, and inhibited the expression of c-myc and Mcl-1 proteins. In contrast, PI3K-selective inhibitors were partially cytostatic in Ras-mutated tumor cell lines, inhibiting cell proliferation by at most 60-90%. PI3K-selective inhibitors also failed to induce significant increases in caspase activity, inhibit eIF-4E phosphorylation, or inhibit c-myc and Mcl-1 expression. Conclusion: We have discovered novel multiplex PI3K inhibitors that demonstrate potent anti-tumor activity in Ras-mutant tumors via inhibition of eIF-4E-mediated protein translation. 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 4491.