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Inhibiting the inhibitors

Nature Reviews Cancer volume 7, page 5 (2007)Cite this article

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The BH3-only proteins bind and inhibit anti-apoptotic proteins such as BCL2, BCL-XL and MCL1 through the interaction of the BH3 domain with a hydrophobic groove in the anti-apoptotic proteins. ABT-737 is a small molecule inhibitor that mimics the BH3 domain and so negates the function of these anti-apoptotic proteins.

Michael Andreeff and colleagues confirmed, using cell-free assays, that ABT-737 binds both BCL2 and BCL-XL but not MCL1. They then showed that acute myeloid leukaemia (AML) cells that express MCL1 are relatively resistant to the drug, and that either doxorubicin or cytosine arabinoside — drugs that are routinely used to treat patients with AML — in combination with ABT-737 are synergistic in inducing the death of AML cell lines. The authors went on to show that the phosphorylation status of BCL2 can determine sensitivity to ABT-737. Extracellular signal-regulated kinase (ERK) phosphorylates BCL2, and the inhibition of ERK increased cell death. Moreover, a mutant form of BCL2 that functions as a constitutively phosphorylated protein reduced sensitivity to ABT-737. However, ERK also phosphorylates the MCL1 PEST sequence, which prevents the rapid turnover of the protein. Inactivation of ERK in combination with ABT-737 induced high levels of cell death, indicating that the suppression of BCL2 phosphorylation and reduced levels of MCL1 (owing to increased degradation) profoundly affect cell sensitivity to ABT-737. Finally, these authors showed that ABT-737 monotherapy preferentially kills primary AML cells in vitro, possibly because normal haematopoietic cells express relatively increased levels of MCL1. Moreover, ABT-737 might preferentially kill AML stem cells, and is able to prolong the survival of mice with leukaemia.

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References

ORIGINAL RESEARCH PAPERS

  1. Konopleva, M. et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375–388 (2006)

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  2. van Delft, M. F. et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389–399 (2006)

    Article  CAS  Google Scholar 

FURTHER READING

  1. Fesik, S. Promoting apoptosis as a strategy for cancer drug discovery. Nature Rev. Cancer 5, 876–885 (2005)

    Article  CAS  Google Scholar 

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Authors
  1. Nicola McCarthy
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McCarthy, N. Inhibiting the inhibitors. Nat Rev Cancer 7, 5 (2007). https://doi.org/10.1038/nrc2052

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