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.
Highlights
Ibrutinib is a small-molecule Bruton’s tyrosine kinase (BTK) inhibitor approved for clinical use in several B-cell malignancies, including chronic lymphocytic leukemia (CLL)
Since BTK is expressed in myeloid cells, we evaluated ibrutinib in acute myeloid leukemia (AML)
To determine the relevance of BTK as a therapeutic target in AML, we examined the protein and mRNA expression of BTK in a panel of AML cell lines
Summary
Ibrutinib is a small-molecule Bruton’s tyrosine kinase (BTK) inhibitor approved for clinical use in several B-cell malignancies, including chronic lymphocytic leukemia (CLL). Inhibition of BTK induces cell death by blocking constitutive B-cell receptor (BCR) signaling and impairing tumor-microenvironment interactions in CLL cells [1, 2]. BTK is expressed in almost all B-hematopoietic malignancies, but is expressed in myeloid cells and myeloid malignancies where it can be activated through mechanisms distinct from BCR signaling. Since BTK is expressed in myeloid cells, we evaluated ibrutinib in acute myeloid leukemia (AML). Other groups reported increased expression and constitutive activation of BTK in AML cell lines and primary AML patient samples [4,5,6,7,8]. We further characterized the anti-AML activity of ibrutinib and identified drugs that sensitize AML cells to ibrutinib. Through exploration of the synergistic activity of ibrutinib with other drugs, we uncovered a BTKindependent role for ibrutinib with potential clinical utility in AML
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