Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.

By M. Konopleva, R. Contractor, T. Tsao, I. Samudio, P. Ruvolo, S. Kitada, Xingming Deng, D. Zhai, Yue-xi Shi, T. Sneed and 16 more. Cancer Cell, 2006

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BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/94c615190b194305c99a00e7df2af509175f1e66

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Citations in the corpus

BCL-2 family antagonists for cancer therapy (2008, background): “This dependency on low MCL1 levels for efficacy has been found in a large panel of cell types including acute myeloid leukaemia cell”
mir-29 regulates Mcl-1 protein expression and apoptosis (2007, background): “Mcl-1 overexpression is commonly observed in cancers (Konopleva et al., 2006), including cholangiocarcinoma (Kobayashi et al.”
Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy (2017, background): “However, the expression of Mcl-1, another important anti-apoptotic protein, renders leukemia cells resistant to both ABT and its predecessor ABT-737 (Konopleva et al., 2006; Pan et al., 2014, 2015).”
Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. (2012, background): “In preclinical in vivo models, both ABT-737 and navitoclax display synergy with cytotoxic agents and targeted therapies against other lymphoproliferative diseases(5,14) and malignancies.(3,34) Along with the promising single-agent activity observed in this study of heavily pretreated patients, such ”
Functional and physical interaction between Bcl‐XL and a BH3‐like domain in Beclin‐1 (2007, background): “…to the demolition of cellular structures and organelles, autophagy is a slow, localized phenomenon in which parts of the cytoplasm are sequestered within double-membraned autophagic vacuoles and finally digested by lysosomal hydrolases (Gozuacik and Kimchi, 2004; Kroemer and Jaattela, 2005).”
The Bcl-2 apoptotic switch in cancer development and therapy (2007, background): “Studies with the BH3 mimetic drug ABT-737 (see below) are also consistent with this model (Konopleva et al., 2006; van Delft et al., 2006; Willis et al., 2007).”
Efficacy and Biological Correlates of Response in a Phase 2 Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia (2016, neutral): “0 3 (9) 1 14 (44) 2 14 (44) Missing 1 (3)”
ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. (2008, result): “in a cellular context and is consistent with previous observations with ABT-737 (7, 11, 13, 14, 26).”