An Introduction to Terminology and Methodology of Chemical Synergy—Perspectives from Across Disciplines

Roell, Kyle; Reif, David M.; Motsinger‐Reif, Alison A.

doi:10.3389/fphar.2017.00158

Cited by 219 publications

(183 citation statements)

References 57 publications

(109 reference statements)

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“…where E c is the effect of the combination of two drugs (A and B) at given doses (a and b) [24]. The response to drug A at dose a is E a and E b indicates the effect of drug B at dose b. Deviation in observed effect greater than the expected effect determined from the reference model is considered a synergistic interaction; a negative deviation is considered an antagonistic combination.…”

Section: Cell Proliferation Assaysmentioning

confidence: 99%

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

et al. 2020

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Objective: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. Results: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3–1.25 µM) and ATRi (0.8–2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3–1.25 µM) and Chk1i(0.05–1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

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Section: Cell Proliferation Assaysmentioning

confidence: 99%

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

et al. 2020

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“…Previous studies reported that combining osimertinib with an alternative RTK inhibitor may inhibit or treat the development of resistance driven by that specific RTK (7-9), whereas simultaneous inhibition of multiple parallel RTKs with osimertinib may be required to effectively potentiate osimertinib action (8). Further, while many studies show enhanced drug activity in combination therapies versus osimertinib treatment alone, they do not assess whether the effects of the 2-drug combinations are truly synergistic; synergistic interactions between therapeutics allow for maximization of the therapeutic effect while minimizing adverse events and may be required for effective therapeutic combinations with targeted agents (40). SOS1 is a common downstream mediator of RTK signaling.…”

Section: Sos1 Inhibition Synergizes With Egfr-tkis To Inhibit Cell Sumentioning

confidence: 99%

Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

Theard

Sheffels

Sealover

et al. 2020

Preprint

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Drug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR-and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.of RAS, co-targeting intermediates of the RAF/MEK/ERK and PI3K/AKT pathways enhances of osimertinib effectiveness, however, signaling through the uninhibited effector pathway may drive resistance (17)(18)(19)(20). Thus, it may be important for therapeutic combinations including osimertinib to stifle all downstream RTK/RAS signaling to be effective.Recent studies suggest that pharmacologic assessments of targeted therapeutics should be performed under 3D culture conditions rather than in 2D adherent cultures (21,22). 3D spheroids show altered growth characteristics, changes in cell surface proteins, altered metabolism, changes in activation of signaling pathways or altered responses to targeted pathway inhibitors, and are more resistant to drug-induced apoptosis compared to 2D adherent cultures signaling (23-26). These differences may be particularly relevant in EGFR-mutated NSCLC. EGFR-mutated cells show differential RTK expression and phosphorylation in 3D versus 2Dconditions (27). Further, EGFR-mutated cells respond more robustly to first-generation EGFR-TKIs in 3D cultures, and these responses more closely resemble responses seen in vivo (28).These data highlight the need for pharmacologic assessment of therapeutics designed to treat EGFR-mutated NSCLC under 3D culture conditions. The ubiquitously expressed RasGEFs (guanine nucleotide exchange factors) SOS1 and SOS2 (son of sevenless 1 and 2) are common signaling intermediates of RTK-mediated RAS activation. Although not initially considered as drug targets because of the low oncogenic potential of SOS (29), there has been renewed interest in SOS proteins as therapeutic targets for cancer treatment. We and others have shown that SOS1 and SOS2 may be important therapeutic targets in KRAS-mutated cancer cells (30-32), and a specific SOS1 inhibitor (BAY-293) has recently been identified (33). Here, we investigate SOS1 and SOS2 as potential therapeutic targets in EGFR-mutated l...

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“…In the next, we put the multi-parametric optimization outputs into the context of existing synergistic concepts as conceived in the biomedical and farmacological studies of the simultaneous effects of therapeutic drugs (see e.g. [61,62]). Despite many alternative measures and approaches have been already proposed, the synergistic quantification of the optimization outputs is not straightforward.…”

Section: Synergistic Quantification Of Optimization Resultsmentioning

confidence: 99%

A new conceptual framework for the therapy by optimized multidimensional pulses of therapeutic activity. The case of multiple myeloma model

Horváth

Brutovsky

2018

Journal of Theoretical Biology

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We developed simulation methodology to assess eventual therapeutic efficiency of exogenous multiparametric changes in a four-component cellular system described by the system of ordinary differential equations. The method is numerically implemented to simulate the temporal behavior of a cellular system of multiple myeloma cells. The problem is conceived as an inverse optimization task where the alternative temporal changes of selected parameters of the ordinary differential equations represent candidate solutions and the objective function quantifies the goals of the therapy. The system under study consists of two main cellular components, tumor cells and their cellular environment, respectively. The subset of model parameters closely related to the environment is substituted by exogenous time dependencies - therapeutic pulses combining continuous functions and discrete parameters subordinated thereafter to the optimization. Synergistic interaction of temporal parametric changes has been observed and quantified whereby two or more dynamic parameters show effects that absent if either parameter is stimulated alone. We expect that the theoretical insight into unstable tumor growth provided by the sensitivity and optimization studies could, eventually, help in designing combination therapies.

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An Introduction to Terminology and Methodology of Chemical Synergy—Perspectives from Across Disciplines

Cited by 219 publications

References 57 publications

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

A new conceptual framework for the therapy by optimized multidimensional pulses of therapeutic activity. The case of multiple myeloma model

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