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Cancer Therapy: Preclinical

Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737

Keryn M. Lucas, Nethia Mohana-Kumaran, Diana Lau, Xu Dong Zhang, Peter Hersey, David C. Huang, Wolfgang Weninger, Nikolas K. Haass and John D. Allen
Keryn M. Lucas
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Nethia Mohana-Kumaran
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Diana Lau
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Xu Dong Zhang
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Peter Hersey
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David C. Huang
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Wolfgang Weninger
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Nikolas K. Haass
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DOI: 10.1158/1078-0432.CCR-11-1166
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Abstract

Purpose: Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a small-molecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL, and BCL-w and shows promise for treating leukemia, lymphoma, and small-cell lung cancer. Melanoma cells are insensitive to ABT-737, but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound.

Experimental Design: The efficacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by short hairpin RNA–mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a three-dimensional organotypic spheroid model, and an in vivo model.

Results: MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 but, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in three-dimensional melanoma spheroids through reduced NOXA expression, although experiments with both xenografts and three-dimensional spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics.

Conclusion: Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers. Clin Cancer Res; 18(3); 1–13. ©2011 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received May 3, 2011.
  • Revision received November 5, 2011.
  • Accepted December 6, 2011.
  • ©2011 American Association for Cancer Research.
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Published OnlineFirst January 20, 2012
doi: 10.1158/1078-0432.CCR-11-1166

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Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737
Keryn M. Lucas, Nethia Mohana-Kumaran, Diana Lau, Xu Dong Zhang, Peter Hersey, David C. Huang, Wolfgang Weninger, Nikolas K. Haass and John D. Allen
Clin Cancer Res January 20 2012 DOI: 10.1158/1078-0432.CCR-11-1166

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Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737
Keryn M. Lucas, Nethia Mohana-Kumaran, Diana Lau, Xu Dong Zhang, Peter Hersey, David C. Huang, Wolfgang Weninger, Nikolas K. Haass and John D. Allen
Clin Cancer Res January 20 2012 DOI: 10.1158/1078-0432.CCR-11-1166
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Clinical Cancer Research
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