The Novel SMAC Mimetic Birinapant Exhibits Potent Activity against Human Melanoma Cells

Krepler, Clemens; Chunduru, Srinivas K.; Halloran, Molly B.; He, Xijing; Xiao, Min; Vultur, Adina; Villanueva, Jessie; Mitsuuchi, Yasuhiro; Neiman, Eric M.; Benetatos, Christopher A.; Nathanson, Katherine L.; Amaravadi, Ravi K.; Pehamberger, Hubert; McKinlay, Mark A.; Herlyn, Meenhard

doi:10.1158/1078-0432.ccr-12-2518

Cited by 88 publications

(89 citation statements)

References 43 publications

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“…We further tested an additional Smac mimetic, birinapant, which was recently reported to induce efficient degradation of both cIAP1 and cIAP2. 28 Similar to BV6, birinapant also exhibited limited cIAP2 degradation in H1299 cells, and cIAP2 depletion, but not cIAP1 depletion, decreased H1299 cell viability upon TNFα and birinapant treatment ( Supplementary Figures S1a and b). Overall, these observations suggest that cIAP2 induction and stabilization by TNFα may inhibit Smac mimetic-induced apoptosis in certain cancer cell lines.…”

Section: Resultsmentioning

confidence: 89%

“…25,26 While several studies have supported hypotheses for how cIAP2 survives in the presence of Smac mimetics, numerous independent studies have also shown that cIAP2 can be efficiently degraded by Smac mimetics in various cell lines. [27][28][29][30][31][32] These observations suggest the existence of other factors that specifically regulate cIAP2 stability upon Smac mimetic treatment. In this study, we propose a new mechanism involving USP11-mediated cIAP2 regulation.…”

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confidence: 88%

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USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Seong

Seo

et al. 2015

Cell Death Differ

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Given their crucial role in apoptosis suppression, inhibitor of apoptosis proteins (IAPs) have recently become attractive targets for cancer therapy. Here, we report that cellular IAP2 (cIAP2) is specifically stabilized in several cancer cell lines, leading to resistance to Smac mimetics, such as BV6 and birinapant. In particular, our results showed that cIAP2 depletion, but not cIAP1 depletion, sensitized cancer cells to Smac mimetic-induced apoptosis. Ubiquitin-specific protease 11 (USP11) is a deubiquitylase that directly stabilizes cIAP2. USP11 overexpression is frequently found in colorectal cancer and melanoma and is correlated with poor survival. In our study, cancer cell lines expressing high levels of USP11 exhibited strong resistance to Smac mimetic-induced cIAP2 degradation. Furthermore, USP11 downregulation sensitized these cells to apoptosis induced by TRAIL and BV6 and suppressed tumor growth in a xenograft model. Finally, the TNFα/JNK pathway induced USP11 expression and maintained cIAP2 stability, suggesting an alternative TNFα-dependent cell survival pathway. Collectively, our data suggest that USP11-stabilized cIAP2 may serve as a barrier against IAP-targeted clinical approaches.

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Section: Resultsmentioning

confidence: 89%

mentioning

confidence: 88%

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

Seong

Seo

et al. 2015

Cell Death Differ

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“…Mean and SEM of 17 individual CLL samples measured in duplicate or triplicate (samples no. 2,6,8,12,15,17,18,19,24,28,33,36,39,41,43,48,50) 2,6,8,12,15,17,18,19,24,28,33,36,39,41,43,48,50) are shown; *p < 0.05. several solid tumors, 16,35,36,[51][52][53] while another study showed that CLL cells remain resistant against Smac mimetics in the context of CD40 ligand stimulation. 39 Compared with CLL cells, BV6 showed little cytotoxicity against non-malignant B-cells, a finding also reported by other investigators in CLL.…”

Section: Discussionmentioning

confidence: 99%

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

Opel

Schnaiter

Dodier

et al. 2015

Intl Journal of Cancer

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Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-jB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-jB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)a, as zVAD.fmk, necrostatin-1 or TNFa-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world. 1 Key prognostic factors besides the Rai and Binet stage are chromosomal aberrations like 17p or 11q deletion, TP53 mutation and immunoglobulin heavy-chain variable region gene (IGVH) mutation status. Although individualized therapeutic strategies have been developed, the disease is still incurable. Especially patients with 17p deletion and TP53 mutation have a very poor prognosis. 2 Therefore, new therapeutic targets that act independently of functional p53 in CLL are needed.CLL is characterized by the accumulation of Blymphocytes which has been largely attributed to defective cell death pathways rather than to aberrant proliferation. [3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3. 7 Inhibitor of apoptosis (IAP) proteins are major regulators of cell death and survival processes. X-linked inhibitor of apoptosis (XIAP) acts as direct caspase inhibitor, 8 while cIAP1 and -2 were shown to protect cells from cell death by acting primarily as E3 ubiquitin liga...

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“…22,23 Here, we found that TNF-a combined with the Smac-mimetic GT13072, an analog of TetraLogic's lead Smacmimetic drug birinapant (formerly TL32711), which is in phase 2 clinical trials and being developed for both solid tumors and hematologic malignancies as a single agent, 30 significantly induced cell death in Pkd1 null MEK cells ( Figure 2A) (P,0.001) and postnatal Pkd1 homozygous PN24 cells ( Figure 2B) (P,0.001). Importantly, Smac-mimetic plus TNF-a induced cell death in epithelial cells obtained from primary The effect of TNF-a (50 ng/ml) and/or Smac-mimetic (1 or 5 mM) on MEK cell viability.…”

Section: Tnf-a Exerts a Prosurvival Effect On Pkd1mentioning

confidence: 99%

Smac-Mimetic–Induced Epithelial Cell Death Reduces the Growth of Renal Cysts

Fan

Zhou

Sweeney

et al. 2013

Journal of the American Society of Nephrology

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Past efforts to pharmacologically disrupt the development and growth of renal cystic lesions focused primarily on normalizing the activity of a specific signaling molecule, but the effects of stimulating apoptosis in the proliferating epithelial cells have not been well studied. Although benign, ADPKD renal cysts created by the sustained proliferation of epithelial cells resemble tumors, and malignant cell death can be achieved by cotreatment with TNF-a and a mimetic of second mitochondria-derived activator of caspase (Smac). Notably, TNF-a accumulates to high levels in ADPKD cyst fluid. Here, we report that an Smac-mimetic selectively induces TNF-a-dependent cystic renal epithelial cell death, leading to the removal of cystic epithelial cells from renal tissues and delaying cyst formation. In vitro, a Smac-mimetic (GT13072) induced the degradation of cIAP1 that is required but not sufficient for cell death. Cotreatment with TNF-a augmented the formation and activation of the RIPK1-dependent death complex and the degradation and cleavage of FLIP, an inhibitor of caspase-8, in renal cystic epithelial cells. This approach produced death specifically in Pkd1 mutant epithelial cells, with no effect on normal renal epithelial cells. Moreover, treatment with the Smac-mimetic slowed cyst and kidney enlargement and preserved renal function in two genetic strains of mice with Pkd1 mutations. Thus, our mechanistic data characterize an apoptotic pathway, activated by the selective synergy of an Smac-mimetic and TNF-a in renal cyst fluid, that attenuates cyst development, providing an innovative translational platform for the rational development of novel therapeutics for ADPKD.

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The Novel SMAC Mimetic Birinapant Exhibits Potent Activity against Human Melanoma Cells

Cited by 88 publications

References 43 publications

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

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

Smac-Mimetic–Induced Epithelial Cell Death Reduces the Growth of Renal Cysts

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