Abstract 4492: Targeting Ras-mutated tumors with novel multiplex PI3K inhibitors
Authors: Hamilton Mark , Fraser Heidi , Bernardino Alexandra , Murga Jose , Paul Dorothy , de Muys Jean-Marc , Han Amy , Rotshteyn Yakov , Qian Dapeng 
Published: June 2012

Background: The simultaneous dysregulation of both PI3K and Ras-MAPK pathways is characteristic of some of the most aggressive forms of human cancer (e.g. tumors with Ras mutations). It has been demonstrated in preclinical studies that effective treatment of Ras-mutated tumors requires blockade of both pathways. Therefore, the ability to achieve this outcome with a single agent holds great clinical promise. One key function of the PI3K and Ras-MAPK pathways is the regulation of protein translation. Both pathways converge to regulate eIF-4E, a key factor in cap-dependent translation of mRNAs encoding critical proteins involved in tumorigenesis and tumor cell survival (e.g. c-Myc and Mcl-1). The PI3K pathway activates eIF-4E via mTOR-mediated phosphorylation and suppression of 4E-BP1, a negative regulator of eIF-4E; the Ras-MAPK pathway modulates eIF4E function through phosphorylation by MNK. It has recently been demonstrated that MNK expression and MNK-dependent phosphorylation of eIF-4E on Ser209 are required for Ras-induced oncogenic transformation, and for tumor development and progression in vivo. Using a combination of rational drug design and conditional lethal screening, we discovered a novel lead series of small molecule inhibitors with multiplex activities against PI3K, mTOR and MNK. Aspects of the preclinical characterization of these novel multiplex PI3K inhibitors will be presented.

Methods and Results: Multiplex PI3K inhibitors are potent inhibitors of tumor cell proliferation and this anti-proliferative activity is independent of the presence of oncogenic mutations (e.g. Ras, PI3K, B-Raf or EGFR). Multiplex PI3K inhibitors effectively induced cell killing of tumor cell lines, including those with Ras mutations, at concentrations ranging from 100 nM to single digit μM, and are superior to either PI3K or MEK inhibitors used alone or in combination. Mechanistically, multiplex PI3K inhibitors inhibit the phosphorylation of AKT, 4E-BP1, ribosomal S6 and eIF-4E, inhibit the expression of c-Myc and Mcl-1 proteins, and induce caspase activity. In human tumor xenograft efficacy studies, multiplex PI3K inhibitors demonstrated robust in vivo anti-tumor activity. The levels of key pharmacodynamic endpoints (phosphorylated AKT, 4E-BP1, ribosomal S6 and eIF-4E) were significantly reduced in treated tumors, consistent with the proposed mechanism of action.

Conclusion: Newly-discovered novel multiplex PI3K inhibitors are capable of simultaneously targeting both PI3K and Ras-MAPK pathways and exhibit potent anti-tumor activity in Ras-mutated tumors. These inhibitors warrant further investigation for development as a potentially novel class of anti-cancer drugs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4492. doi:10.1158/1538-7445.AM2011-4492