Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism
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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
Aaron D. Schimmer, e-mail: [email protected]
Keywords: AML, BTK, ibrutinib, ethacridine lactate, PARG
Received: July 29, 2015 Accepted: November 16, 2015 Published: November 27, 2015
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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