Transcriptional Modulation by Idelalisib Synergizes with Bendamustine in Chronic Lymphocytic Leukemia

Kost Kost,Mejia Mejia,Johnston Johnston,Bouchard Bouchard,Katyal Katyal,Saleh Saleh,Marshall Marshall,Banerji Banerji,Mostafizar Mostafizar,Gibson Gibson

doi:10.3390/cancers11101519

Abstract

The phosphatidyl-inositol 3 kinase (PI3K) δ inhibitor, idelalisib (IDE), is a potent inhibitor of the B-cell receptor pathway and a novel and highly effective agent for the treatment of chronic lymphocytic leukemia (CLL). We evaluated the activities of IDE in comparison to bendamusine (BEN), a commonly used alkylating agent, in primary CLL cells ex vivo. In contrast to BEN, IDE was cytotoxic to cells from extensively-treated patients, including those with a deletion (del)17p. Cross-resistance was not observed between BEN and IDE, confirming their different modes of cytotoxicity. Marked synergy was seen between BEN and IDE, even in cases that were resistant to BEN or IDE individually, and those with deletion (del) 17p. CD40L/interleukin 4 (IL4) co-treatment mimicking the CLL microenvironment increased resistance to IDE, but synergy was retained. PI3Kδ-deficient murine splenic B cells were more resistant to IDE and showed reduced synergy with BEN, thus confirming the importance of functional PI3Kδ protein. Although IDE was observed to induce γH2AX, IDE did not enhance activation of the DNA damage response nor DNA repair activity. Interestingly, IDE decreased global RNA synthesis and was antagonistic with 5,6-Dichlorobenzimidazole 1-b-D-ribofuranoside (DRB), an inhibitor of transcription. These findings add to the increasingly complex cellular effects of IDE, and B cell receptor (BCR) inhibitors in general, in CLL.

Highlights

Most patients with chronic lymphocytic leukemia (CLL) will require therapy at some point during their disease course, and typically receive chemoimmunotherapy as initial treatment [1]
In the present study we have evaluated the cytotoxicity of IDE in primary CLL cells ex vivo, demonstrating a lack of cross-resistance between this agent and chemotherapy, significant cross-resistance between IDE and IBR and a decrease in IDE activity when the microenvironment was simulated with CD40L/interleukin 4 (IL4)
We have demonstrated that inhibition of PI3Kδ by IDE is cytotoxic to primary CLL cells, with the sensitivity of cells differing to that of the standard chemotherapeutic agents, BEN, CLB and FLU

Summary

Introduction

Most patients with chronic lymphocytic leukemia (CLL) will require therapy at some point during their disease course, and typically receive chemoimmunotherapy as initial treatment [1]. Standard treatments include alkylating agents (chlorambucil, CLB; bendamustine, BEN), or nucleoside analogues. BEN is a bifunctional alkylating agent with a mechanism unique from other alkylating agents, such as CLB [2,3]. We and others have previously demonstrated that BEN is synergistic with FLU in primary CLL cells, and this synergy was related to increased DNA damage [2,4]. The algorithm for therapy has recently shifted, with the advent of novel targeted therapies [1,5]. These therapies include the B cell receptor (BCR) pathway inhibitors, ibrutinib (IBR) and idelalisib (IDE), which target Bruton’s tyrosine kinase (BTK) and the δ isoform of phosphatidyl-inositol

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Discussion

Conclusion