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

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.

A Subset of Patients with Acute Myeloid Leukemia Has Leukemia Cells Characterized by Chemokine Responsiveness and Altered Expression of Transcriptional as well as Angiogenic Regulators

“…Our present study shows that a subset of patients has chemokine-responsive AML cells, and similar dual-targeting may be possible in AML. This hypothesis is supported by recent studies; ibrutinib has direct antileukemic effects in human AML ( 40 ) and is in addition able to alter chemokine-dependent AML cell migration ( 41 ). Our present studies therefore suggest combined targeting of AML cell survival, and migration (i.e., chemokine targeting) should be considered for patients with chemokine-responsive AML cells.…”

Role of Bruton’s tyrosine kinase in B cells and malignancies

“…Suggested mechanism: increased intracellular ROS production in cells treated with combination. [ 256 ] ND-2158 (IRAK4 inhibitor) ABC-DLBCL - ABC-DLBCL cell lines OCI-Ly10 and TMD8 - OCI-Ly10 xenografts MYD88-IRAK4 signaling is important for ABC- DLBCL viability Combination was more effective than ND-2158 alone in inhibiting IKK activity, enhancing apoptosis, and blocking tumor growth in mice. [ 257 ] PU-H71 (Binds to tumor enhanced HSP90 complexes) ABC-DLBCL DLBCL cell lines (HBL-1 and TMD8) teHSP90 complexes are associated with tumor survival.…”

The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia

“…Recently, one study indicated that ibrutinib combined with ethacridine had a synergistic cytotoxicity to AML cells [24]. Interestingly, Pillinger et al and Wu et al found ibrutinib was particularly effective in inhibiting FLT3-ITD mutant AML cell survival [25, 26].…”