The BH3-mimetic ABT-737 sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance

Wroblewski, David, Mijatov, Branka, Mohana- Kumaran, Nethia, Lai, Fritz, Gallagher, Stuart J., Haass, Nikolas K., Zhang, Xu Dong and Hersey, Peter (2013) The BH3-mimetic ABT-737 sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance. Carcinogenesis, 34 2: 237-247. doi:10.1093/carcin/bgs330


Author Wroblewski, David
Mijatov, Branka
Mohana- Kumaran, Nethia
Lai, Fritz
Gallagher, Stuart J.
Haass, Nikolas K.
Zhang, Xu Dong
Hersey, Peter
Title The BH3-mimetic ABT-737 sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance
Journal name Carcinogenesis   Check publisher's open access policy
ISSN 0143-3334
1460-2180
Publication date 2013-02
Year available 2012
Sub-type Article (original research)
DOI 10.1093/carcin/bgs330
Open Access Status
Volume 34
Issue 2
Start page 237
End page 247
Total pages 11
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2014
Language eng
Abstract Although the introduction of selective v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors has been a major advance in treatment of metastatic melanoma, approximately 50% of patients have limited responses including stabilization of disease or no response at all. This study aims to identify a novel means of overcoming resistance of melanoma to killing by BRAF inhibitors. We examined the influence of the BH3-mimetic ABT-737 on induction of apoptosis by the selective BRAF inhibitor PLX4720 in melanoma cells with or without BRAF V600E mutation. Included were cell lines established from four patients before and during treatment with selective BRAF inhibitors and 3D spheroids derived from these cell lines. Cell lines with no or low sensitivity to PLX4720 underwent synergistic increases and increased rates of apoptosis when combined with ABT-737. This degree of synergism was not seen in cell lines without BRAF V600E mutations. Apoptosis was mediated through the mitochondrial pathway and was due in part to upregulation of Bim as shown by inhibition of apoptosis following small interfering RNA knockdown of Bim. Similar effects were seen in cell lines established from patients prior to treatment but not in lines from patients clinically resistant to the selective BRAF inhibitors and in 3D spheroids derived from these cell lines. These results suggest that combination of selective BRAF inhibitors with ABT-737 or the related orally available compound ABT-263 may increase the degree and rate of responses in previously untreated patients with V600E melanoma but not in those with acquired resistance to these agents.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ
Additional Notes Published online 20 October 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
UQ Diamantina Institute Publications
 
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Created: Sat, 08 Mar 2014, 12:04:44 EST by Nikolas Haass on behalf of UQ Diamantina Institute