Charting the Fragmented Landscape of Drug Synergy

Overview

Journal Trends Pharmacol Sci

Specialty Pharmacology

Date 2020 Mar 2

PMID 32113653

Citations 40

Authors

Christian T Meyer

David J Wooten

Carlos F Lopez

Vito Quaranta

Affiliations

Soon will be listed here.

Abstract

Even as the clinical impact of drug combinations continues to accelerate, no consensus on how to quantify drug synergy has emerged. Rather, surveying the landscape of drug synergy reveals the persistence of historical fissures regarding the appropriate domains of conflicting synergy models - fissures impacting all aspects of combination therapy discovery and deployment. Herein we chronicle the impact of these divisions on: (i) the design, interpretation, and reproducibility of high-throughput combination screens; (ii) the performance of algorithms to predict synergistic mixtures; and (iii) the search for higher-order synergistic interactions. Further progress in each of these subfields hinges on reaching a consensus regarding the long-standing rifts in the field.

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References

Johnson E, Office E, Kawate T, Orzechowski M, Hung D . Large-Scale Chemical-Genetic Strategy Enables the Design of Antimicrobial Combination Chemotherapy in . ACS Infect Dis. 2019; 6(1):56-63. PMC: 6958538. DOI: 10.1021/acsinfecdis.9b00373. View

Cokol M, Kuru N, Bicak E, Larkins-Ford J, Aldridge B . Efficient measurement and factorization of high-order drug interactions in . Sci Adv. 2017; 3(10):e1701881. PMC: 5636204. DOI: 10.1126/sciadv.1701881. View

Eduati F, Doldan-Martelli V, Klinger B, Cokelaer T, Sieber A, Kogera F . Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type-Specific Dynamic Logic Models. Cancer Res. 2017; 77(12):3364-3375. PMC: 6433282. DOI: 10.1158/0008-5472.CAN-17-0078. View

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

Comandante-Lou N, Khaliq M, Venkat D, Manikkam M, Fallahi-Sichani M . Phenotype-based probabilistic analysis of heterogeneous responses to cancer drugs and their combination efficacy. PLoS Comput Biol. 2020; 16(2):e1007688. PMC: 7055924. DOI: 10.1371/journal.pcbi.1007688. View

Van der Borght K, Tourny A, Bagdziunas R, Thas O, Nazarov M, Turner H . BIGL: Biochemically Intuitive Generalized Loewe null model for prediction of the expected combined effect compatible with partial agonism and antagonism. Sci Rep. 2017; 7(1):17935. PMC: 5738392. DOI: 10.1038/s41598-017-18068-5. View

Tang J, Wennerberg K, Aittokallio T . What is synergy? The Saariselkä agreement revisited. Front Pharmacol. 2015; 6:181. PMC: 4555011. DOI: 10.3389/fphar.2015.00181. View

Wooten D, Meyer C, Lubbock A, Quaranta V, Lopez C . MuSyC is a consensus framework that unifies multi-drug synergy metrics for combinatorial drug discovery. Nat Commun. 2021; 12(1):4607. PMC: 8322415. DOI: 10.1038/s41467-021-24789-z. View

Chantzi E, Jarvius M, Niklasson M, Segerman A, Gustafsson M . COMBImage2: a parallel computational framework for higher-order drug combination analysis that includes automated plate design, matched filter based object counting and temporal data mining. BMC Bioinformatics. 2019; 20(1):304. PMC: 6549340. DOI: 10.1186/s12859-019-2908-0. View

10.

Russ D, Kishony R . Additivity of inhibitory effects in multidrug combinations. Nat Microbiol. 2018; 3(12):1339-1345. PMC: 6295580. DOI: 10.1038/s41564-018-0252-1. View

11.

Santolini M, Barabasi A . Predicting perturbation patterns from the topology of biological networks. Proc Natl Acad Sci U S A. 2018; 115(27):E6375-E6383. PMC: 6142275. DOI: 10.1073/pnas.1720589115. View

12.

Dean Z, Maltas J, Wood K . Antibiotic interactions shape short-term evolution of resistance in E. faecalis. PLoS Pathog. 2020; 16(3):e1008278. PMC: 7093004. DOI: 10.1371/journal.ppat.1008278. View

13.

Fang H, Chen X, Pei X, Grant S, Tan M . Experimental design and statistical analysis for three-drug combination studies. Stat Methods Med Res. 2015; 26(3):1261-1280. DOI: 10.1177/0962280215574320. View

14.

Gupta V, Dixit N . Trade-off between synergy and efficacy in combinations of HIV-1 latency-reversing agents. PLoS Comput Biol. 2018; 14(2):e1006004. PMC: 5833289. DOI: 10.1371/journal.pcbi.1006004. View

15.

Bulusu K, Guha R, Mason D, Lewis R, Muratov E, Kalantar Motamedi Y . Modelling of compound combination effects and applications to efficacy and toxicity: state-of-the-art, challenges and perspectives. Drug Discov Today. 2015; 21(2):225-38. DOI: 10.1016/j.drudis.2015.09.003. View

16.

Palmer A, Sorger P . Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy. Cell. 2017; 171(7):1678-1691.e13. PMC: 5741091. DOI: 10.1016/j.cell.2017.11.009. View

17.

Tang J, Gautam P, Gupta A, He L, Timonen S, Akimov Y . Network pharmacology modeling identifies synergistic Aurora B and ZAK interaction in triple-negative breast cancer. NPJ Syst Biol Appl. 2019; 5:20. PMC: 6614366. DOI: 10.1038/s41540-019-0098-z. View

18.

Maltas J, Wood K . Pervasive and diverse collateral sensitivity profiles inform optimal strategies to limit antibiotic resistance. PLoS Biol. 2019; 17(10):e3000515. PMC: 6834293. DOI: 10.1371/journal.pbio.3000515. View

19.

Anchang B, Davis K, Fienberg H, Williamson B, Bendall S, Karacosta L . DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity. Proc Natl Acad Sci U S A. 2018; 115(18):E4294-E4303. PMC: 5939057. DOI: 10.1073/pnas.1711365115. View

20.

Wood K, Nishida S, Sontag E, Cluzel P . Mechanism-independent method for predicting response to multidrug combinations in bacteria. Proc Natl Acad Sci U S A. 2012; 109(30):12254-9. PMC: 3409729. DOI: 10.1073/pnas.1201281109. View