Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia

Schirmer, Melanie; Trentin, Luca; Queudeville, Manon; Seyfried, Felix; Demir, Salih; Tausch, Eugen; Stilgenbauer, Stephan; Eckhoff, Sarah Mirjam; Meyer, Lueder Hinrich; Debatin, Klaus‐Michael

doi:10.1038/cddis.2015.382

Cited by 21 publications

(24 citation statements)

References 41 publications

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“…Attempts to improve outcomes of primary high-risk disease by intensification of existing treatment, while largely successful, carry the burden of high toxicity (43,44), thus highlighting the need for targeted therapies that could be incorporated to strengthen current combination chemotherapy regimens. Similar to a recent study using BV6 (45) combining birinapant with an induction-type regimen (VXL) significantly enhanced objective responses and prolonged leukemia regressions in two Ph-like PDXs in vivo . Importantly, no additional side effects were observed when birinapant was combined with VXL combination therapy in vivo .…”

Section: Discussionsupporting

confidence: 75%

Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant

et al. 2016

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Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of induction-type regimen of vincristine, dexamethasone and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment.

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Section: Discussionsupporting

confidence: 75%

Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant

et al. 2016

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“…Coincubation with Etanercept significantly blocked cell death induced by SMs (Fig. d ) pointing toward a critical role of the TNF/TNFR1‐axis in SM‐induced cell death in line with previous reports . However, Etanercept is the only clinically available anti‐TNF therapy which, in addition to TNF, also blocks LTA .…”

Section: Resultssupporting

confidence: 87%

“…We identify SMs to be potent inducers of cell death in a subset of BCP‐ALL samples in line with previous reports . Interestingly, we also found that BCP‐ALL primograft samples with low or intermediate sensitivity to SM treatment are sensitized to SM‐induced killing in presence of an inhibitor of caspase activity, including Emricasan, a pan‐caspase inhibitor in clinical trials for liver cirrhosis .…”

Section: Discussionsupporting

confidence: 90%

“…Response to SM‐induced cell death has recently been identified to be dependent on a cell's capability of undergoing both, apoptosis and necroptosis in a receptor interacting protein kinase (RIPK)1‐dependent manner . Analysis of RIPK1 and RIPK3 protein expression in SM‐sensitive and SM‐insensitive samples did not reveal any differences in expression levels between the two groups (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

“…SMs AT406, LCL161 and Birinapant are currently undergoing clinical evaluation in advanced solid tumors and a range of hematological malignancies, for example, multiple myeloma or B‐cell lymphoma. In pediatric BCP‐ALL, SMs are still in preclinical evaluation with so far encouraging results as subsets of primary BCP‐ALL showed high sensitivity to SM‐induced cell death ex vivo and in vivo . As stand‐alone agents, SMs proved limited efficacy in patients in other cancer entities which is why a successful clinical implementation of these compounds is likely to require ( i ) combinatorial treatment regimens that enhance SM‐induced killing of cancer cells and ( ii ) identification of those patients with SM‐sensitive tumors before start of therapy, ideally via biomarkers.…”

Section: Discussionmentioning

confidence: 99%

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Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B‐cell acute lymphoblastic leukemia

Zinngrebe

Schlichtig

Kraus

et al. 2019

Intl Journal of Cancer

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Second mitochondria‐derived activator of caspase (SMAC) mimetics (SMs) targeting inhibitor of apoptosis proteins (IAPs) activate cell death pathways, and are currently being evaluated in clinical trials. Their successful therapeutic implementation requires upfront identification of patients who could benefit from a SM‐based treatment but biomarkers for SM sensitivity have not yet been described. Here, we analyzed the intrinsic activity of two monovalent (AT406 and LCL161) and two bivalent (Birinapant and BV6) SMs on unselected patient‐derived pediatric precursor B‐cell acute lymphoblastic leukemia (BCP‐ALL) identifying a subset of patient samples to be particularly sensitive to SM‐induced cell death. This subset was defined by a characteristic gene expression signature with 127 differentially regulated genes, amongst them TNFRSF1A encoding TNFR1, and a critical role of TNFR1 in SM‐induced cell death in sensitive BCP‐ALL was confirmed on the functional level. Interestingly, samples with intermediate or low sensitivity to SMs were sensitized to SM‐induced cell death by inhibition of caspases using zVAD.fmk or Emricasan, a pan‐caspase inhibitor in clinical trials. When we compared our expression data to published data sets, we identified an overlap of four genes to be commonly differentially regulated in SM‐sensitive BCP‐ALL, that is, TSPAN7, DIPK1C, MTX2 and, again, TNFRSF1A. Functional testing revealed that this set of genes identified samples with high sensitivity to SM treatment. In summary, our data suggest using this gene signature as biomarker predicting response to SM treatment and point to the development of new combinatorial treatments consisting of SMs and pan‐caspase inhibitors for a successful clinical implementation of SMs in treatment of BCP‐ALL.

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Proteasome inhibitors and Smac mimetics cooperate to induce cell death in diffuse large B‐cell lymphoma by stabilizing NOXA and triggering mitochondrial apoptosis

Dietz

Dalda

Zielke

et al. 2020

Intl Journal of Cancer

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Copy number gains and increased expression levels of cellular Inhibitor of Apoptosis protein (cIAP)1 and cIAP2 have been identified in primary diffuse large B-cell lymphoma (DLBCL) tissues. Second mitochondria-derived activator of caspases (Smac) mimetics were designed to antagonize IAP proteins. However, since their effect as single agents is limited, combination treatment represents a strategy for their clinical development. Therefore, we investigated the Smac mimetic BV6 in combination with proteasome inhibitors and analyzed the molecular mechanisms of action. We discovered that BV6 treatment sensitizes DLBCL cells to proteasome inhibition. We show a synergistic decrease in cell viability and induction of apoptosis by BV6/Carfilzomib (CFZ) treatment, which was confirmed by calculation of combination index (CI) and Bliss score. BV6 and CFZ acted together to trigger activation of BAX and BAK, which facilitated cell death, as knockdown of BAX and BAK significantly reduced BV6/CFZ-mediated cell death. Activation of BAX and BAK was accompanied by loss of mitochondrial membrane potential (MMP) and activation of caspases. Pretreatment with the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Aspfluoromethylketone (zVAD.fmk) rescued BV6/CFZ-induced cell death, confirming caspase dependency. Treatment with CFZ alone or in combination with BV6 caused accumulation of NOXA, which was required for cell death, as gene silencing by siRNA or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated NOXA inactivation inhibited BV6/CFZinduced cell death. Together, these experiments indicate that BV6 and CFZ cooperatively induce apoptotic cell death via the mitochondrial pathway. These findings emphasize the role of Smac mimetics for sensitizing DLBCL cells to proteasome inhibition with important implications for further (pre)clinical studies. M.V. and S.F. shared equally to the senior authorship.

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Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia

Cited by 21 publications

References 41 publications

Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant

Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant

Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B‐cell acute lymphoblastic leukemia

Proteasome inhibitors and Smac mimetics cooperate to induce cell death in diffuse large B‐cell lymphoma by stabilizing NOXA and triggering mitochondrial apoptosis

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