Targeting mitochondrial apoptotic priming state to personalize therapy for relapsed acute myeloid leukemia

The majority of relapsed acute myeloid leukemia (AML) patients still succumb to disease despite improvements in therapy. We present landscapes of pharmacologic sensitivity for 22 AML patient-derived xenograft (PDX) models together with genomic and transcriptomic profiles. First, we used ex vivo dynamic BH3 profiling (DBP) to segregate PDXs according to prior treatment status and accurately predicted in vivo efficacy of drugs with varying mechanisms of action. We next selected in vivo acquired resistance to single agents of distinct mechanisms, which caused broad chemoresistance across all models associated with a reduction in mitochondrial apoptotic priming. DBP could identify drugs with persistent in vivo activity even in these resistant models. Using RNA-seq, we found conserved gene expression signatures defining relapsed phenotypes common to mechanistically distinct agents targeting FLT-3, BCL2, IAPs, and BRD-4. We replicated drug-response patterns from PDX models in primary and relapsed AML patients, demonstrating the clinical feasibility of such approach Overall design: To investigate the mechanism of acquired drug resistance, an unbiased whole transcriptomic analysis on a total of 78 resistant samples from three PDX models (DFAM-61786, DFAM-15354, and DFAM-61345) and 16 matched-control samples was conducted.