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

Lucas, KM; Mohana-Kumaran, N; Lau, D; Zhang, XD; Hersey, P; Huang, DC; Weninger, W; Haass, NK; Allen, JD

Author(s): Lucas, KM; Mohana-Kumaran, N; Lau, D; Zhang, XD; Hersey, P; Huang, DC; Weninger, W; Haass, NK; Allen, JD;
Details: Publication Year 2012-02-01,Volume 18,Issue #3,Page 783-795
Journal Title: CLINICAL CANCER RESEARCH
Publication Type: Journal Article
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); 783-95. (C)2011 AACR.
Publisher: AMER ASSOC CANCER RESEARCH
Keywords: BH3 MIMETIC ABT-737; EFFICIENTLY INDUCES APOPTOSIS; COLORECTAL-CANCER CELLS; CHEMOTHERAPEUTIC-AGENTS; MALIGNANT-MELANOMA; LUNG-CANCER; IN-VITRO; BCL-2/BCL-X-L/BCL-W INHIBITOR; SELECTIVE INHIBITOR; MULTIPLE-MYELOMA
Research Division(s): Chemical Biology
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-11-1166

Creation Date: 2012-02-01 12:00:00

Last Modified: 2015-03-18 08:23:08