Data from Cell and Molecular Determinants of <i>In Vivo</i> Efficacy of the BH3 Mimetic ABT-263 against Pediatric Acute Lymphoblastic Leukemia Xenografts

Abstract

<div>Abstract<p><b>Purpose:</b> Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict <i>in vivo</i> ABT-263 sensitivity.</p><p><b>Experimental Design:</b> The <i>in vivo</i> efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An <i>in vitro</i> coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of <i>in vivo</i> ABT-263 sensitivity.</p><p><b>Results:</b> ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among <i>BCL2</i> family members, <i>in vivo</i> ABT-263 sensitivity correlated best with low <i>MCL1</i> mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an <i>in vitro</i> coculture assay, a predictive model of <i>in vivo</i> ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted <i>in vivo</i> ABT-263 responses with high sensitivity (50%) and specificity (100%).</p><p><b>Conclusion:</b> These results highlight the <i>in vivo</i> efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of <i>in vitro</i> functional assays can be used to predict its <i>in vivo</i> efficacy. <i>Clin Cancer Res; 20(17); 4520–31. ©2014 AACR</i>.</p></div>