A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia

Abstract

Evasion of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL), calling for new strategies to bypass resistance. Here, we provide first evidence that small-molecule X-linked inhibitor of apoptosis (XIAP) inhibitors in combination with the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) present a novel approach to trigger apoptosis in CLL, including subgroups with resistant disease or unfavorable prognosis. XIAP, cellular IAP (cIAP) 1, and cIAP2 are expressed at high levels in primary CLL samples. Proof-of-concept studies in CLL cell lines show that subtoxic concentrations of XIAP inhibitors significantly enhance TRAIL-induced apoptosis and also sensitize for CD95-mediated apoptosis. Importantly also in primary CLL samples, XIAP inhibitor acts in concert with TRAIL to trigger apoptosis in 18 of 27 (67%) cases. This XIAP inhibitor-induced and TRAIL-induced apoptosis involves caspase-3 activation and is blocked by the caspase inhibitor zVAD.fmk. The cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct subgroups of patients with poor prognostic features (i.e., with 17p deletion, TP53 mutation, chemotherapy-refractory disease, or unmutated V H genes). Interestingly, cases with unmutated V H genes were significantly more sensitive to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with V H gene-mutated samples, pointing to a role of B-cell receptor signaling in apoptosis regulation. By showing that XIAP inhibitors in combination with TRAIL present a new strategy to trigger apoptosis even in resistant forms and poor prognostic subgroups of CLL, our findings have important implications for the development of apoptosis-based therapies in CLL. [Cancer Res 2009;69(23):8977-86]

RIP1 Protein-dependent Assembly of a Cytosolic Cell Death Complex Is Required for Inhibitor of Apoptosis (IAP) Inhibitor-mediated Sensitization to Lexatumumab-induced Apoptosis

“…Thus, by demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent and TNF␣-independent manner in RMS cells, our findings have important implications for the development of experimental treatment strategies for RMS. Beyond RMS, this study, together with our previous reports (18,(35)(36)(37)(38), underscores the broader relevance of the concept of simultaneously targeting IAP proteins and TRAIL receptors as a promising anticancer strategy.…”

“…The concept of simultaneously targeting IAP proteins and TRAIL receptors is, in principle, suitable for clinical translation because IAP antagonists and anti-TRAIL receptor antibodies have individually already entered the stage of early clinical evaluation (33,34). In addition, we previously reported that IAP inhibitors preferentially prime various cancer types, but not non-malignant cells, to TRAIL receptor-induced apoptosis, pointing to some cancer selectivity (35)(36)(37). Thus, by demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent and TNF␣-independent manner in RMS cells, our findings have important implications for the development of experimental treatment strategies for RMS.…”

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

“…While some other studies using different Smac mimetics reported no correlation between cell death induction by Smac mimetic and biological parameters in primary CLL, 39,40 two studies using IAP inhibitors plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) showed cell death induction in CLL cases with poor prognosis. 13,41 Using whole-genome gene expression profiling, we identify two functional categories that are most significantly modulated by BV6, i.e., programmed cell death and NF-jB pathway, across tumor entities not only in CLL but also in primary CBF AML samples, underlining the broader relevance of this finding. Concomitant experiments demonstrate that treatment with BV6 activates NF-jB signaling and cell death pathways in primary CLL cells.…”

“…IAP proteins, in particular XIAP, are overexpressed in CLL and this overexpression confers chemoresistance and is associated with a progressive course. [11][12][13][14] To counter IAP proteins several small-molecule IAP inhibitors, including Smac mimetics, have been developed. 15 It has been shown that Smac mimetics abrogate XIAP-mediated caspase inhibition and induce autoubiquitination and rapid proteasomal degradation of cIAP1 and-2, leading to activation of NF-jB and TNFa production that triggers cell death in an autocrine/paracrine fashion.…”

“…15,19 Investigating the therapeutic potential of the bivalent Smac mimetic BV6 in CLL is of high interest, as our previous experiments showed that inhibition of IAP proteins increases death receptor-induced apoptosis in primary CLL cells, markedly in subgroups with bad prognosis including patients with 17p deletion. 13 Therefore, we aimed in our study to better understand the mechanisms of Smac mimetic-induced cell death in CLL and to identify parameters of responsiveness to Smac mimetics in CLL.…”