Charting the Fragmented Landscape of Drug Synergy

Meyer, Christian A.; Wooten, David J.; López, Carlos F.; Quaranta, Vito

doi:10.1016/j.tips.2020.01.011

Cited by 59 publications

(74 citation statements)

References 65 publications

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“…Here in some cases synergy of active ingredients is desired [5], in order to achieve the desired effect at lower dose, which means that the effect of the compound combination is higher than that expected in case of the null hypothesis of additivity. Multiple models exist for this purpose, such as the Loewe model (which assumes additivity of effects), the Bliss model (which assumes independence) and the Highest Single Agent (HSA) model, which only takes the most significant effect into account (as well as other more recent models [6,7] which in some cases show more intuitive behavior in practice). However, given that the mechanistic reason for synergy is in most cases poorly understood, the model choice is often empirical, which can lead to conclusions that a compound combination is synergistic due to the model chosen, which wouldn't have been the case with another model (see [7] for a more detailed discussion of this subject).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Pruteanu¹,

Kopanitsa²,

Módos

et al. 2020

PLoS ONE

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Pathway analysis is an informative method for comparing and contrasting drug-induced gene expression in cellular systems. Here, we define the effects of the marine natural product fucoxanthin, separately and in combination with the prototypic phosphatidylinositol 3kinase (PI3K) inhibitor LY-294002, on gene expression in a well-established human glioblastoma cell system, U87MG. Under conditions which inhibit cell proliferation, LY-294002 and fucoxanthin modulate many pathways in common, including the retinoblastoma, DNA damage, DNA replication and cell cycle pathways. In sharp contrast, we see profound differences in the expression of genes characteristic of pathways such as apoptosis and lipid metabolism, contributing to the development of a differentiated and distinctive drug-induced gene expression signature for each compound. Furthermore, in combination, fucoxanthin synergizes with LY-294002 in inhibiting the growth of U87MG cells, suggesting complementarity in their molecular modes of action and pointing to further treatment combinations. The synergy we observe between the dietary nutraceutical fucoxanthin and the synthetic chemical LY-294002 in producing growth arrest in glioblastoma, illustrates the potential of nutripharmaceutical combinations in targeting this challenging disease.

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Section: Introductionmentioning

confidence: 99%

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Pruteanu¹,

Kopanitsa²,

Módos

et al. 2020

PLoS ONE

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“…Conversely, at dosages limited by toxicities, synergistic drug combinations achieve higher efficacies than their non-synergistic counterparts. Synergy is thought to arise typically as the result of downstream interactions between the steps/pathways targeted by the drugs (Fitzgerald et al, 2006;Meyer et al, 2020Meyer et al, , 2019Zimmermann et al, 2007). The synergy we predict here is thus surprising because the two entry pathways targeted are independent.…”

Section: Introductionmentioning

confidence: 75%

“…Synergy between drugs implies that their combined effect is more than their individual effects added together (Fitzgerald et al, 2006;Meyer et al, 2020Meyer et al, , 2019Zimmermann et al, 2007). Synergistic drug combinations are preferable because they allow the realization of the desired efficacy with lower net drug exposure, thus reducing toxicity.…”

Section: Introductionmentioning

confidence: 99%

Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

Padmanabhan¹,

Desikan²,

Dixit³

2020

Preprint

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The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through ‘repurposing’ drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry.

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“…To compare drug sensitivity among cell lines while correcting for differences in their baseline proliferation rates, drug-induced normalized growth rates (a.k.a. DIP rates 36 ) were computed as follows: 49 . Using this framework, we identify any interaction that causes the combination of two drugs to be more effective in reducing the net growth rate (via either inhibition of cell division or induction of cell death) than either of the constituent drugs without drawing a distinction between synergism, additivity or even sub-additive effects.…”

Section: Measurements Of Growth Rate Drug Sensitivity and Combinatiomentioning

confidence: 99%

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

Khaliq

Manikkam

Martínez

et al. 2020

Preprint

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The hyperactivation of MAPK signaling pathway motivates the clinical use of MAPK inhibitors to treat BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency and diminishes the efficacy of MAPK inhibitors. To identify key regulators of such variability and potential mitigation strategies, we screened 276 epigenetic-modifying compounds, individually and in combination with MAPK inhibitors, across both genetically distinct and isogenic populations of melanoma cells. Integrated with single-cell analysis and multivariate modeling, we identified three classes of epigenetic inhibitors that target seemingly distinct epigenetic states associated with either one of the lysine-specific histone demethylases KDM1A, or KDM4B, or BET bromodomain proteins. While melanocytes remained insensitive, the anti-tumor efficacy of each inhibitor was predicted based on a melanoma cell's differentiation state and MAPK activity. Our systems pharmacology approach highlights an avenue toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.

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Charting the Fragmented Landscape of Drug Synergy

Cited by 59 publications

References 65 publications

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

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