SynergyFinder 3.0: an interactive analysis and consensus interpretation of multi-drug synergies across multiple samples

Aittokallio, Tero

doi:10.1093/nar/gkac382

Cited by 301 publications

(194 citation statements)

References 31 publications

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“…To better define the dose-response landscape for this interaction, Bliss synergy analysis was performed on the MGX-FK506 dataset ( Figure S2 ). Robust synergy (Bliss score 13.97) was seen across the landscape with a value of 40.5 calculated for the most synergistic area [ 43 ]. Of significance from the therapeutic perspective, combination exposure also converted the fungistatic activity of the individual agents to fungicidal.…”

Section: Resultsmentioning

confidence: 99%

Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens

Liston

Whitesell

Kapoor

et al. 2022

JoF

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Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Addressing this need, fosmanogepix (N-phosphonooxymethylene prodrug of manogepix; MGX) is the first in a new class of gepix drugs, and acts as a broad-spectrum, orally bioavailable inhibitor of the essential fungal glycosylphosphatidylinositol (GPI) acyltransferase Gwt1. MGX inhibits the growth of diverse fungal pathogens and causes accumulation of immature GPI-anchored proteins in the fungal endoplasmic reticulum. Relevant to the ongoing clinical development of fosmanogepix, we report a synergistic, fungicidal interaction between MGX and inhibitors of the protein phosphatase calcineurin against important human fungal pathogens. To investigate this synergy further, we evaluated a library of 124 conditional expression mutants covering 95% of the genes encoding proteins involved in GPI-anchor biosynthesis or proteins predicted to be GPI-anchored. Strong negative chemical-genetic interactions between the calcineurin inhibitor FK506 and eleven GPI-anchor biosynthesis genes were identified, indicating that calcineurin signalling is required for fungal tolerance to not only MGX, but to inhibition of the GPI-anchor biosynthesis pathway more broadly. Depletion of these GPI-anchor biosynthesis genes, like MGX treatment, also exposed fungal cell wall (1→3)-β-D-glucans. Taken together, these findings suggest the increased risk of invasive fungal infections associated with use of calcineurin inhibitors as immunosuppressants may be mitigated by their synergistic fungicidal interaction with (fos)manogepix and its ability to enhance exposure of immunostimulatory glucans.

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Section: Resultsmentioning

confidence: 99%

Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens

Liston

Whitesell

Kapoor

et al. 2022

JoF

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“…For addressing the question of whether these enhancements were synergistic, a large series of combination experiments with increasing concentrations of the antagonists S63845 and ABT-263 were performed ( Supplementary Figure S3 ). Using the web application SyngeryFinder 3.0 created by Ianevski et al [ 30 ], the enhancement of viability reduction and apoptosis induction in HH and HuT-78 cells was calculated as largely synergistic (δ score > 10). Over larger concentration ranges, the δ score was >40 in HH, and 10–40 in HuT-78, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…As concerning the identification of synergistic effects in combination treatments with S63845 and ABT-263, the program SyngeryFinder 3.0 was used [ 30 ]. In particular, the Bliss scoring method was applied, and delta scores (δ) ≥10 were considered as synergistic, whereas scores between −10 and 10 were considered as additive.…”

Section: Methodsmentioning

confidence: 99%

Sensitivity of Cutaneous T-Cell Lymphoma Cells to the Mcl-1 Inhibitor S63845 Correlates with the Lack of Bcl-w Expression

Sumarni

Zhu

Sinnberg

et al. 2022

IJMS

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Long-term, curative treatment of cutaneous T-cell lymphomas (CTCL) remains a major challenge. Therapy resistance is often based on apoptosis deficiency, and may depend on antiapoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL, Bcl-w and Mcl-1. For their targeting, several antagonists have been generated, which mimic the Bcl-2 homology domain 3 (BH3 mimetics). As dysregulation and overexpression of Mcl-1 has been reported in CTCL, the use of Mcl-1 inhibitors appears as an attractive strategy. Here, we investigated the effects of the selective Mcl-1 inhibitor S63845 in a series of four CTCL cell lines, in comparison to ABT-263 and ABT-737 (inhibitors of Bcl-2, Bcl-xL and Bcl-w). In two cell lines (HH, HuT-78), S63845 resulted in significant apoptosis induction, decrease in cell viability, loss of mitochondrial membrane potential and caspase activation, while two other cell lines (MyLa, SeAx) remained completely resistant. An inverse correlation was found, as S63845-resistant cells were highly sensitive to ABT-263/-737, and S63845-sensitive cells showed only moderate sensitivity to ABTs. Combinations of S63845 and ABT-263 partially yielded synergistic effects. As concerning Bcl-2 protein expression, weaker Mcl-1 expression was found in S63845-resistant MyLa and SeAx, while for Bcl-2 and Bcl-xL, the lowest expression was found in the highly sensitive cell line HH. The most striking difference between S63845-resistant and -sensitive cells was identified for Bcl-w, which was exclusively expressed in S63845-resistant cells. Thus, CTCL may be efficiently targeted by BH3 mimetics, providing the right target is preselected, and Bcl-w expression may serve as a suitable marker.

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“…The expected drug combination responses between EHT1610 and trametinib or EHT1610 and venetoclax were calculated based on the ZIP reference model using SynergyFinder 64 . Deviations between observed and expected responses with positive and negative values denote synergy and antagonism, respectively.…”

Section: In Vitro Drug Synergy Analysismentioning

confidence: 99%

Pharmacologic Inhibition of DYRK1A Results in MYC Hyperactivation and ERK Hyperphosphorylation rendering KMT2A-R ALL Cells Sensitive to BCL2 Inhibition

Hurtz

Ayyadevara

Wertheim

et al. 2022

Preprint

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KMT2A-rearranged (KMT2A-R) B cell acute lymphoblastic leukemia (ALL) is a high-risk disease in children and adults that is often chemotherapy resistant. To identify non-cytotoxic approaches to therapy, we performed a domain-specific kinome-wide CRISPR screen in KMT2A-R cell lines and patient derived xenograft samples (PDX) and identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a potential target. Pharmacologic inhibition of the KMT2A-fusion transcriptional co-regulator Menin released the KMT2A-fusion complex from the DYRK1A promoter thereby lowering DYRK1A expression levels confirming DYRK1A as a direct target of the KMT2A fusion oncogene. Direct pharmacologic inhibition of DYRK1A decreased cell proliferation of KMT2A-R ALL, thereby confirming the requirement of DYRK1A in this ALL subtype. To further understand the biologic function of DYRK1A in KMT2A-R ALL, we leveraged pharmacologic DYRK1A inhibitors in KMT2A-R PDX and cell line models. DYRK1A inhibition consistently led to upregulation of MYC protein levels, and hyperphosphorylation of ERK, which we confirmed via in vivo treatment experiments. Furthermore, DYRK1A inhibition decreased ALL burden in mice. Our results further demonstrate that DYRK1A inhibition induces the proapoptotic factor BIM, but ERK hyperphosphorylation is the driving event that induces cell cycle arrest. In contrast, combined treatment of KMT2A-R ALL cells in vitro and in vivo with DYRK1A inhibitors and the BCL2 inhibitor, venetoclax, synergistically decreases cell survival and reduced the leukemic burden in mice. Taken together these results demonstrate a unique function of DYRK1A specially in KMT2A-R ALL. Synergistic inhibition of DRYK1A and BCL2 may provide a low-toxic approach to treat this high risk ALL subtype.

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SynergyFinder 3.0: an interactive analysis and consensus interpretation of multi-drug synergies across multiple samples

Cited by 301 publications

References 31 publications

Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens

Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens

Sensitivity of Cutaneous T-Cell Lymphoma Cells to the Mcl-1 Inhibitor S63845 Correlates with the Lack of Bcl-w Expression

Pharmacologic Inhibition of DYRK1A Results in MYC Hyperactivation and ERK Hyperphosphorylation rendering KMT2A-R ALL Cells Sensitive to BCL2 Inhibition

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