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Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia

Rongqing Pan1, Leah J Hogdal, Juliana M Benito

  • 1Departments of 1Leukemia, 2Pediatrics, and 3Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 4Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 6The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; 7AbbVie Inc., North Chicago, Illinois; and 8Department of Laboratory Medicine, University of California San Francisco, San Francisco, California; 9Department of Internal Medicine III, University Hospital of Ulm, Ulm; 10MLL Munich Leukemia Laboratory, Munich, Germany.

Cancer Discovery
|December 19, 2013
PubMed

Insights

The anti-cancer drug ABT-199 effectively targets B-cell leukemia/lymphoma 2 (BCL-2) in acute myeloid leukemia (AML) models. This selective BCL-2 inhibitor shows high sensitivity in patient samples, suggesting its potential as an AML therapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Pharmacology

Background:

  • B-cell leukemia/lymphoma 2 (BCL-2) is a key regulator of mitochondrial apoptosis.
  • Identifying tumors sensitive to BCL-2 inhibition is clinically challenging.
  • Acute myeloid leukemia (AML) is a significant hematological malignancy.

Purpose of the Study:

  • To evaluate the efficacy of the selective BCL-2 antagonist ABT-199 in acute myeloid leukemia (AML).
  • To investigate the mechanism of action of ABT-199 in AML.
  • To identify potential predictive biomarkers for ABT-199 treatment in AML.

Main Methods:

  • Treatment of AML cell lines, primary patient samples, and murine xenografts with ABT-199.
  • Assessment of cytotoxicity and IC50 values.
  • Mitochondrial studies utilizing BH3 profiling.
  • Protein profiling analysis.

Main Results:

  • AML cell lines, primary patient samples, and xenografts exhibited high sensitivity to ABT-199.
  • In primary patient cells, the median IC50 was approximately 10 nmol/L, with rapid cell death observed within 2 hours.
  • BH3 profiling confirmed an on-target mitochondrial mechanism of action, correlating with cytotoxicity.

Conclusions:

  • ABT-199 demonstrates significant anti-leukemic activity in preclinical AML models.
  • BH3 profiling and protein analysis show promise as predictive biomarkers for ABT-199 therapy in AML.
  • These findings support the clinical investigation of ABT-199 for AML treatment.

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