Work

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

Year: 2015

Type: article

Abstract: // Lianne E. Rotin 1, 2 , Marcela Gronda 1 , Neil MacLean 1 , Rose Hurren 1 , XiaoMing Wang 1 , Feng-Hsu Lin 1 , Jeff Wrana 3 , Alessandro Datti 3, 4 , Dwayne L. Barber 1 , Mark D. Minden 1, 2 , Malik Slassi 5 , Aaron D. Schimmer 1, 2 1 Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada 2 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 3 Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada 4 Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy 5 Fluorinov Pharma Inc., Toronto, Ontario, Canada Correspondence to: 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 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.6409