Oncotarget

Research Papers:

Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells

Monica Pallis _, Francis Burrows, Jeremy Ryan, Martin Grundy, Claire Seedhouse, Amina Abdul-Aziz, Joan Montero, Anthony Letai and Nigel Russell

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Oncotarget. 2017; 8:16220-16232. https://doi.org/10.18632/oncotarget.8742

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Abstract

Monica Pallis1, Francis Burrows2, Jeremy Ryan3, Martin Grundy1, Claire Seedhouse4, Amina Abdul-Aziz4, Joan Montero3, Anthony Letai3, Nigel Russell1,4

1Clinical Haematology, Nottingham University Hospitals, Nottingham, UK

2Tragara Pharmaceuticals, Carlsbad, CA, USA

3Department of Medical Oncology, Harvard Medical School, Boston, MA, USA

4Department of Haematology, University of Nottingham, Nottingham, UK

Correspondence to:

Monica Pallis, e-mail: monica.pallis@nottingham.ac.uk

Keywords: BAD, NOXA, TG02, ABT-199, AML

Received: January 04, 2016     Accepted: March 28, 2016     Published: April 15, 2016

ABSTRACT

Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells. At the concentrations used, the peptides did not trigger mitochondrial outer membrane permeabilisation in their own right, but primed cells to release Cytochrome C in the presence of an appropriate trigger of a complementary pathway. In KG-1a cells TG02 and ABT-199 synergised to induce apoptosis. In heterogeneous AML patient samples we noted a range of sensitivities to the two agents. Although some individual samples markedly favoured one agent or the other, in the group as a whole the combination of TG02 + ABT-199 was significantly more cytotoxic than either agent individually. We conclude that dynamic NOXA and BAD BH3 profiling is a sensitive methodology for investigating molecular pathways of drug action and complementary mechanisms of chemoresponsiveness.


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