TRAIL Signaling and Synergy Mechanisms Used in TRAIL-Based Combination Therapies

Hellwig, Christian T.; Rehm, Markus

doi:10.1158/1535-7163.mct-11-0434

Cited by 123 publications

(128 citation statements)

References 72 publications

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“…Furthermore, TRAIL-induced apoptosis can proceed independent of protein neosynthesis, explaining why a systems analysis of baseline protein expression is sufficient to predict TRAIL responsiveness. As TRAIL ligands are currently investigated in clinical trials and as improved second generation ligands are currently in preclinical development, 30,31 our systems approach may provide possibilities to identify TRAIL-responsive melanoma by molecular profiling, and by extension may assist in patient stratification as part of future clinical trial designs. We also predicted DTIC-induced cell death, albeit with slightly lower accuracy.…”

Section: Discussionmentioning

confidence: 99%

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

et al. 2013

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Many cancer entities and their associated cell line models are highly heterogeneous in their responsiveness to apoptosis inducers and, despite a detailed understanding of the underlying signaling networks, cell death susceptibility currently cannot be predicted reliably from protein expression profiles. Here, we demonstrate that an integration of quantitative apoptosis protein expression data with pathway knowledge can predict the cell death responsiveness of melanoma cell lines. By a total of 612 measurements, we determined the absolute expression (nM) of 17 core apoptosis regulators in a panel of 11 melanoma cell lines, and enriched these data with systems-level information on apoptosis pathway topology. By applying multivariate statistical analysis and multi-dimensional pattern recognition algorithms, the responsiveness of individual cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or dacarbazine (DTIC) could be predicted with very high accuracy (91 and 82% correct predictions), and the most effective treatment option for individual cell lines could be pre-determined in silico. In contrast, cell death responsiveness was poorly predicted when not taking knowledge on protein-protein interactions into account (55 and 36% correct predictions). We also generated mathematical predictions on whether anti-apoptotic Bcl-2 family members or x-linked inhibitor of apoptosis protein (XIAP) can be targeted to enhance TRAIL responsiveness in individual cell lines. Subsequent experiments, making use of pharmacological Bcl-2/Bcl-xL inhibition or siRNA-based XIAP depletion, confirmed the accuracy of these predictions. We therefore demonstrate that cell death responsiveness to TRAIL or DTIC can be predicted reliably in a large number of melanoma cell lines when investigating expression patterns of apoptosis regulators in the context of their network-level interplay. The capacity to predict responsiveness at the cellular level may contribute to personalizing anti-cancer treatments in the future.

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Section: Discussionmentioning

confidence: 99%

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

et al. 2013

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“…Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, Apo-2L) is one of the members of the TNF gene superfamily that selectively induces apoptosis of cancer cells but not of normal cells in various tissue types and is currently in clinical trials for the treatment of human cancers (5,6). Since MM is characterized as a tumor composed of long-surviving rather than fast-growing malignant plasma cells, potentiating apoptosis has been envisaged as a potential therapeutic approach (7).…”

Section: Introductionmentioning

confidence: 99%

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

et al. 2014

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Abstract.Recently, much progress has been achieved in the treatment of multiple myeloma (MM). However, the major challenge of chemotherapeutic drugs is acquired resistance. Oncolytic virotherapies offer promising alternatives; with the possibility of their integration with current therapeutic strategies. In the present study, we assessed the potential of ZD55-TRAIL (an oncolytic adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand) as an oncolytic agent for MM. Our results clearly indicated that ZD55 armed with TRAIL was more cytotoxic to drug-sensitive as well as drug-resistant MM cell lines, than the virus alone. Furthermore, it was also observed that ZD55-TRAIL induced apoptosis through the activation of the caspase pathway. In particular, ZD55-TRAIL significantly inhibited insulin-like growth factor-1 receptor (IGF-1R) and NFκB. However, IGF did not abrogate ZD55-TRAIL-induced cell death. Combination of ZD55-TRAIL with the PI3K inhibitor LY294002 in RPMI-8226 cells inhibited the virus-mediated activation of mTOR and AKT, thus, promoting cell death. Combined treatment of ZD55-TRAIL and MG132 (a proteasome inhibitor) robustly increased the expression of death receptor 5 (DR5), which enhanced the apoptosis response without significant toxicity to normal liver cells. Collectively, our results suggest that combined treatment of TRAIL-armed oncolytic adenovirus and a PI3K inhibitor or a proteosome inhibitor may serve as a promising therapy for MM.

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“…The TRAIL death receptor (DR) 4 and DR5 are exclusively expressed on tumour cells (13). Ligands, including TRAIL, which bind to TRAIL receptors, may selectively activate the death signal in tumour cells (14). However as with numerous therapies, resistance has been identified for this type of therapy; endogenous low expression of DR4 and DR5 is responsible for inherent TRAIL resistance in T-ALL patients (15).…”

Section: N-[mentioning

confidence: 99%

Inhibition of γ-secretase activity synergistically enhances tumour necrosis factor-related apoptosis-inducing ligand induced apoptosis in T-cell acute lymphoblastic leukemia cells via upregulation of death receptor 5

2016

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Abstract. T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematopoietic malignancy prone to relapse and drug resistance. Half of all T-ALL patients exhibit mutations in Notch1, which leads to aberrant Notch1 associated signaling cascades. Notch1 activation is mediated by the γ-secretase cleavage of the Notch1 receptor into the active intracellular domain of Notch1 (NCID). Clinical trials of γ-secretase small molecule inhibitors (GSIs) as single agents for the treatment of T-ALL have been unsuccessful. The present study demonstrated, using immunofluorescence and western blotting, that blocking γ-secretase activity in T-ALL cells with N- [(3,5-difluorophenyl) acetyl]-L-alanyl-2-phenyl] glycine-1,1-dimethylethyl ester (DAPT) downregulated NCID and upregulated the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5). Upregulation of DR5 restored the sensitivity of T-ALL cells to TRAIL. Combination index revealed that the combined treatment of DAPT and TRAIL synergistically enhanced apoptosis compared with treatment with either drug alone. TRAIL combined with the clinically evaluated γ-secretase inhibitor 3-[(1r, 4s)-4-(4-chlorophenylsulfonyl)-4-(2, 5-difluorophenyl) cyclohexyl] propanoic acid (MK-0752) also significantly enhanced TRAIL-induced cell death compared with either drug alone. DAPT/TRAIL apoptotic synergy was dependent on the extrinsic apoptotic pathway and was associated with a decrease in BH3 interacting-domain death agonist and x-linked inhibitor of apoptosis. In conclusion, γ-secretase inhibition represents a potential therapeutic strategy to overcome TRAIL resistance for the treatment of T-ALL.

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TRAIL Signaling and Synergy Mechanisms Used in TRAIL-Based Combination Therapies

Cited by 123 publications

References 72 publications

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

Inhibition of γ-secretase activity synergistically enhances tumour necrosis factor-related apoptosis-inducing ligand induced apoptosis in T-cell acute lymphoblastic leukemia cells via upregulation of death receptor 5

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