Work

Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines

Year: 2016

Type: article

Abstract: // Brian Koss 1 , Jeremy Ryan 2 , Amit Budhraja 1 , Katherine Szarama 1 , Xue Yang 1, 3 , Madhavi Bathina 1 , Michael H. Cardone 4 , Zaneta Nikolovska-Coleska 5 , Anthony Letai 2 , Joseph T. Opferman 1 1 Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA 2 Department of Adult Oncology, The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 3 Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA 4 Eutropics Incorporated, Cambridge, MA, USA 5 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA Correspondence to: Joseph T. Opferman, e-mail: [email protected] Keywords: BH3 mimetics, apoptosis, BCL-2, cancer model, drug development Received: October 12, 2015 Accepted: January 24, 2016 Published: February 05, 2016 ABSTRACT One of the hallmarks of cancer is a resistance to the induction of programmed cell death that is mediated by selection of cells with elevated expression of anti-apoptotic members of the BCL-2 family. To counter this resistance, new therapeutic agents known as BH3-mimetic small molecules are in development with the goal of antagonizing the function of anti-apoptotic molecules and promoting the induction of apoptosis. To facilitate the testing and modeling of BH3-mimetic agents, we have developed a powerful system for evaluation and screening of agents both in culture and in immune competent animal models by engineering mouse leukemic cells and re-programming them to be dependent on exogenously expressed human anti-apoptotic BCL-2 family members. Here we demonstrate that this panel of cell lines can determine the specificity of BH3-mimetics to individual anti-apoptotic BCL-2 family members (BCL-2, BCL-X L , BCL-W, BFL-1, and MCL-1), demonstrate whether cell death is due to the induction of apoptosis (BAX and BAK-dependent), and faithfully assess the efficacy of BH3-mimetic small molecules in pre-clinical mouse models. These cells represent a robust and valuable pre-clinical screening tool for validating the efficacy, selectivity, and on-target action of BH3-mimetic agents.

Source: Oncotarget

DOI: 10.18632/oncotarget.7204