Targeting PI3K, mTOR, ERK, and Bcl-2 signaling network shows superior antileukemic activity against AML ex vivo.

In this study, we show that while inhibition of PI3K, mTOR, and ERK showed superior induction of cell death compared to inhibition of PI3K and mTOR, the levels of cell death were modest in some AML cell lines and primary patient samples tested. Although simultaneous inhibition of PI3K, mTOR, and ERK caused downregulation of Mcl-1 and upregulation of Bim, immunoprecipitation of Bcl-2 revealed increased binding of Bim to Bcl-2, which was abolished by the addition of ABT-199, suggesting that Bim was bound to Bcl-2 which prevented cell death. Treatment with combined VS-5584, SCH772984, and ABT-199 showed significant increase of cell death in AML cell lines and primary patient samples and significant reduction of AML colony formation in primary patient samples, while there was no significant effect on colony formation of normal human CD34+ hematopoietic progenitor cells. Taken together, our findings show that inhibition of PI3K, mTOR, and ERK synergistically induces cell death in AML cells, and addition of ABT-199 enhances cell death further. Thus, our data support targeting the PI3K, mTOR, ERK, and Bcl-2 signaling network for the treatment of AML. PMID: 29208365 [PubMed - as supplied by publisher]
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research