ABSTRACT
Idelalisib is a targeted agent that potently inhibits PI3Kδ which is exclusively expressed in hematological cells. Bendamustine is a well-tolerated cytotoxic alkylating agent which has been extensively used for treatment of chronic lymphocytic leukemia (CLL). Both these agents are FDA-approved for CLL. To increase the potency of idelalisib and bendamustine, we tested their combination in primary CLL lymphocytes. While each compound alone produced a moderate response, combination at several concentrations resulted in synergistic cytotoxicity. Idelalisib enhanced the bendamustine-mediated DNA damage/repair response, indicated by the phosphorylation of ATM, Chk2, and p53. Each drug alone activated γH2AX but combination treatment further increased the expression of this DNA damage marker. Compared with the control, idelalisib treatment decreased global RNA synthesis, resulting in a decline of early-response and short-lived MCL1 transcripts. In concert, there was a decline in total Mcl-1 protein in CLL lymphocytes. Isogenic mouse embryonic fibroblasts lacking MCL1 had higher sensitivity to bendamustine alone or in combination compared to MCL1 proficient cells. Collectively, these data indicate that bendamustine and idelalisib combination therapy should be investigated for treating patients with CLL.
Subject(s)
Bendamustine Hydrochloride/pharmacology , DNA Damage , Purines/pharmacology , Quinazolinones/pharmacology , Animals , Antineoplastic Agents/pharmacology , Cell Line , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Dose-Response Relationship, Drug , Drug Synergism , Embryo, Mammalian/cytology , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression Regulation, Leukemic/drug effects , Humans , Immunoblotting , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Mice, Knockout , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, CulturedABSTRACT
Idelalisib [Zydelig (Gilead Sciences, Inc.), also known as CAL-101 and GS-1101] was approved in 2014 in the United States and European Union for the treatment of three indolent B-cell neoplasms: relapsed/refractory chronic lymphocytic leukemia (CLL, in combination with rituximab), relapsed follicular lymphoma, and relapsed small lymphocytic lymphoma (as monotherapy). Furthermore, it was approved in the European Union as first-line therapy for poor-prognosis CLL with 17p deletions or TP53 mutations and in patients unsuitable for chemoimmunotherapy. Idelalisib is an orally bioavailable ATP-competitive kinase inhibitor that targets the PI3K p110 isoform δ (PI3Kδ) with high potency and selectivity. PI3Kδ is hyperactivated in B-cell malignancies and plays a pivotal role in the B-cell receptor pathway, a key oncogenic driver in B-cell malignancies. The near exclusive expression of the PI3Kδ isoform in hematopoietic cells and the selectivity of idelalisib for the PI3Kδ isoform are essential for its efficacy and tolerability, even in elderly patients unfit for chemotherapy. Idelalisib is the first PI3K inhibitor approved by the regulatory agencies; this approval will change the treatment landscape of indolent B-cell malignancies.
