Oncotarget

Research Papers:

Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells

Martin Grundy _, Sahana Balakrishnan, Matthew Fox, Claire H. Seedhouse and Nigel H. Russell

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Oncotarget. 2018; 9:37777-37789. https://doi.org/10.18632/oncotarget.26540

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Abstract

Martin Grundy1, Sahana Balakrishnan2, Matthew Fox2, Claire H. Seedhouse2 and Nigel H. Russell1,2

1Clinical Haematology, Nottingham University Hospitals, Nottingham, United Kingdom

2Department of Haematology, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom

Correspondence to:

Martin Grundy, email: m.grundy@nottingham.ac.uk

Keywords: AML; BCL-2; MCL-1; Venetoclax; S63845

Received: November 19, 2018     Accepted: December 20, 2018     Published: December 28, 2018

ABSTRACT

Acute myeloid leukaemia (AML) cells often up-regulate pro-survival members of the BCL-2 protein family, such as BCL-2 and MCL-1, to avoid apoptosis. Venetoclax (ABT-199) targets BCL-2 and has shown promising efficacy in AML but over-expression of MCL-1 can cause resistance. A co-operative approach, targeting both BCL-2 and MCL-1 may therefore prove beneficial. This study investigated the potential synergistic relationship between Venetoclax and the MCL-1 inhibitor S63845 in AML cells. We treated MV4-11 cells and primary AML samples for 4 hours with Venetoclax, S63845 or the combination. We used a short-term flow cytometric technique to assess synergy using cytochrome C release as a read out of response. The combination of Venetoclax and S63845 produced a synergistic apoptotic response in MV4-11 cells and primary samples, including the leukaemia re-populating leukaemic stem cell (LSC) population, in 92% of the samples. Known molecular biomarkers of response to BCL-2 and MCL-1 targeting agents were corroborated, and augmented, with the short-term functional assay. The assay also predicted potential biomarkers of response to the combination of BCL-2 and MCL-1 targeting agents. Primary samples with an IDH2_140 mutation were more sensitive to Venetoclax as a single agent whereas samples with a FLT3-ITD mutation were more resistant. This resistance could be reversed when combined with S63845. All FLT3-ITD and NPM1 mutated samples were sensitive to the combination of drugs.

We report that co-operatively targeting BCL-2 and MCL-1 may be beneficial in AML and a short-term in vitro assay can identify patients who might best respond to this combination.


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