Oncotarget

Research Papers:

Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism

Lianne E. Rotin, Marcela Gronda, Neil MacLean, Rose Hurren, XiaoMing Wang, Feng-Hsu Lin, Jeff Wrana, Alessandro Datti, Dwayne L. Barber, Mark D. Minden, Malik Slassi and Aaron D. Schimmer _

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Oncotarget. 2016; 7:2765-2779. https://doi.org/10.18632/oncotarget.6409

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Abstract

Lianne E. Rotin1,2, Marcela Gronda1, Neil MacLean1, Rose Hurren1, XiaoMing Wang1, Feng-Hsu Lin1, Jeff Wrana3, Alessandro Datti3,4, Dwayne L. Barber1, Mark D. Minden1,2, Malik Slassi5, Aaron D. Schimmer1,2

1Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

2Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

3Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada

4Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy

5Fluorinov Pharma Inc., Toronto, Ontario, Canada

Correspondence to:

Aaron D. Schimmer, e-mail: aaron.schimmer@utoronto.ca

Keywords: AML, BTK, ibrutinib, ethacridine lactate, PARG

Received: July 29, 2015     Accepted: November 16, 2015     Published: November 27, 2015

ABSTRACT

Targeting Bruton’s tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease.


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