The development of acquired resistance to chemotherapy in the clinic remains a major obstacle to improve patient outcome and a better understanding of the underlying molecular events is essential to target refractory cancers, including leukemia. Infants with acute lymphoblastic leukemia involving translocations of the mixed-lineage leukemia (MLL) gene have a poorer prognosis than other age groups and this has been attributed to early relapse and resistance to traditional chemotherapies. The purpose of this study was to assess the in vivo sensitivity and mechanisms of resistance of a panel of 8 MLL xenografts established from primary biopsies in immune-deficient (NOD/SCID) mice to the BH3-mimetic and Bcl-2, Bcl-XL and Bcl-W inhibitor ABT-263. Leukaemia engraftment and progression were assessed by flow cytometric enumeration of the proportion of human CD45+ cells in the peripheral blood at weekly intervals. ABT-263 (100 mg/kg daily × 21 per oral gavage) significantly delayed the progression of 8/8 xenografts compared with vehicle-treated controls (p < 0.05), with progression delayed by between 2 and 27 days across the entire panel. However, quantification of Bcl-2 protein family members by immunoblot did not reveal that expression of a single member significantly correlated with in vivo ABT-263 sensitivity. Continuous ABT-263 treatment of xenografts in vivo resulted in the outgrowth of 5 independent ABT-263-resistant xenograft lines. Resistance was confirmed to be approximately 15-fold compared with passage-matched controls by in vitro cytotoxicity assay (n = 6; p < 0.0001). Subsequent inoculation of ABT-263-selected xenograft lines into NOD/SCID mice also confirmed their in vivo resistance compared with passage-matched controls. ABT-263-selected lines showed a 5-fold increase in cell viability compared with passage-matched control lines after 4 days of ex vivo culture (p = 0.02). Moreover, the ABT-263-selected cells were significantly resistant in vitro to 2 established drugs used in the treatment of pediatric acute lymphoblastic leukemia, dexamethasone (p = 0.001) and daunorubicin (p = 0.006). This cell death-resistant phenotype could not be attributed to altered protein expression of known ABT-263 resistance modifiers, including Bcl-2, Mcl-1 and Bim. In conclusion, this study has demonstrated that ABT-263 has significant in vivo efficacy against MLL xenografts derived from direct patient explants, but that ABT-263 resistance can readily arise in vivo leading to a cell death-resistant phenotype via a unique mechanism. (Supported in part by NCI NO1CM42216)

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 LB-23. doi:10.1158/1538-7445.AM2011-LB-23

©2011 American Association for Cancer Research
2011