Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

被引：221

作者：

Menden, Michael P. ^{[1
,2
,19
]}

Wang, Dennis ^{[1
,3
]}

Mason, Mike J. ^{[4
]}

Szalai, Bence ^{[5
,6
,7
,8
]}

Bulusu, Krishna C. ^{[1
]}

Guan, Yuanfang ^{[9
]}

Yu, Thomas ^{[4
]}

Kang, Jaewoo ^{[10
]}

Jeon, Minji ^{[10
]}

Wolfinger, Russ ^{[11
]}

Nguyen, Tin ^{[12
]}

Zaslavskiy, Mikhail ^{[13
]}

Jang, In Sock ^{[4
]}

Ghazoui, Zara ^{[1
]}

Ahsen, Mehmet Eren ^{[14
]}

Vogel, Robert ^{[14
]}

Neto, Elias Chaibub ^{[4
]}

Norman, Thea ^{[4
]}

Tang, Eric K. Y. ^{[1
]}

Garnett, Mathew J. ^{[15
]}

Di Veroli, Giovanni Y. ^{[16
]}

Fawell, Stephen ^{[17
]}

Stolovitzky, Gustavo ^{[14
,18
]}

Guinney, Justin ^{[4
]}

Dry, Jonathan R. ^{[17
]}

Saez-Rodriguez, Julio ^{[2
,8
,20
]}

Abante, Jordi ^{[21
]}

Abecassis, Barbara Schmitz ^{[22
]}

Aben, Nanne ^{[23
,24
]}

Aghamirzaie, Delasa ^{[25
]}

Aittokallio, Tero ^{[26
]}

Akhtari, Farida S. ^{[27
]}

Al-lazikani, Bissan ^{[28
]}

Alam, Tanvir ^{[29
]}

Allam, Amin ^{[30
]}

Allen, Chad ^{[31
]}

de Almeida, Mariana Pelicano ^{[22
]}

Altarawy, Doaa ^{[32
,33
]}

Alves, Vinicius ^{[34
]}

Amadoz, Alicia ^{[35
]}

Anchang, Benedict ^{[36
]}

Antolin, Albert A. ^{[28
]}

Ash, Jeremy R. ^{[37
]}

Romeo Aznar, Victoria ^{[38
]}

Ba-alawi, Wail ^{[29
]}

Bagheri, Moeen ^{[39
]}

Bajic, Vladimir ^{[29
]}

Ball, Gordon ^{[40
]}

Ballester, Pedro J. ^{[41
,42
,43
,44
]}

Baptista, Delora ^{[45
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Oncol, Cambridge SG8 6EH, England

[2] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England

[3] Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield S10 2TN, S Yorkshire, England

[4] Sage Bionetworks, Seattle, WA 98121 USA

[5] Semmelweis Univ, Fac Med, Dept Physiol, H-1085 Budapest, Hungary

[6] Hungarian Acad Sci, Lab Mol Physiol, H-1085 Budapest, Hungary

[7] Semmelweis Univ MTA SE, H-1085 Budapest, Hungary

[8] Rhein Westfal TH Aachen, Fac Med, Joint Res Ctr Computat Biomed, D-52062 Aachen, Germany

[9] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[10] Korea Univ, Dept Comp Sci & Engn, Seoul 02841, South Korea

[11] SAS Inst Inc, Cary, NC 27513 USA

[12] Univ Nevada, Dept Comp Sci & Engn, Reno, NV 89557 USA

[13] Owkin Inc, Computat Biol, New York, NY 10022 USA

[14] IBM Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA

[15] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[16] AstraZeneca, IMED Biotech Unit, Early Clin Dev, Cambridge SG8 6EH, England

[17] R&D Boston, AstraZeneca, IMED Biotech Unit, Oncol, Waltham, MA 02451 USA

[18] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[19] Helmholtz Zentrum MUnchen, Inst Computat Biol, German Res Ctr Environm Hlth, D-85764 Munich, Germany

[20] Heidelberg Univ, Fac Med, Inst Computat Biomed, D-69120 Heidelberg, Germany

[21] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA

[22] BiGCaT NUTRIM Maastricht Univ, Dept Bioinformat, NL-6229 ER Maastricht, Netherlands

[23] Div Mol Carcinogenesis NKI, NL-1066 CX Amsterdam, Netherlands

[24] Delft Univ Technol, Fac EEMCS, NL-2628 CD Delft, Netherlands

[25] Virginia Tech, Genet Bioinformat & Computat Biol, Blacksburg, VA 24061 USA

[26] Univ Helsinki, Inst Mol Med Finland FIMM, FI-00014 Helsinki, Finland

[27] North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA

[28] Inst Canc Res, London SW3 6JB, England

[29] KAUST, CBRC, Thuwal 23955, Saudi Arabia

[30] KAUST, Thuwal 23955, Saudi Arabia

[31] Univ Cambridge, Ctr Mol Informat, Dept Chem, Cambridge CB2 1EW, England

[32] Virginia Tech, Dept Comp Sci, Blacksburg, VA 24061 USA

[33] Alexandria Univ, Alexandria 21500, Egypt

[34] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[35] Igenomix SL, Dept Bioinformat, Valencia 46980, Spain

[36] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA

[37] North Carolina State Univ, Bioinformat Res Ctr, Dept Chem, Dept Stat, Raleigh, NC 27695 USA

[38] Leloir Inst, C1405 BWE, Buenos Aires, DF, Argentina

[39] Univ Toronto, Toronto, ON M5S, Canada

[40] Karolinska Inst, Dept Med, Unit Computat Med, Solna SciLifeLab,Ctr Mol Med, SE-17176 Solna, Sweden

[41] INSERM U1068, F-13005 Marseille, France

[42] Inst Paoli Calmettes, F-13009 Marseille, France

[43] Aix Marseille Univ, F-13007 Marseille, France

[44] CNRS UMR7258, F-13273 Marseille, France

[45] Univ Minho, Ctr Biol Engn CEB, P-4710057 Braga, Portugal

[46] Inst HyperCube, F-92907 Paris, France

[47] Genome Inst Singapore, Computat & Syst Biol, Singapore 138672, Singapore

[48] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA

[49] RIKEN Japan, Ctr Integrat Med Sci, Kobe, Hyogo 6500047, Japan

[50] Canc Genom Netherlands, NL-3584 CG Utrecht, Netherlands

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国惠康基金; 欧盟地平线“2020”;

关键词：

ANDROGEN RECEPTOR; BREAST-CANCER; GENE; CELL; INHIBITION; RESISTANCE; PATHWAY; MUTATIONS; LANDSCAPE; RESOURCE;

D O I：

10.1038/s41467-019-09799-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.

引用

页数：17

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