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

AstraZeneca-Sanger Drug Combination DREAM Consortium

doi:10.1038/s41467-019-09799-2

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

AstraZeneca-Sanger Drug Combination DREAM Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	2674
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09799-2
Publication status	Published - 1 Dec 2019

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@article{a781bfb599db419f93881d696a1e0d17,

title = "Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen",

abstract = "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{\textquoteright}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.",

author = "Menden, {Michael P.} and Dennis Wang and Mason, {Mike J.} and Bence Szalai and Bulusu, {Krishna C.} and Yuanfang Guan and Thomas Yu and Jaewoo Kang and Minji Jeon and Russ Wolfinger and Tin Nguyen and Mikhail Zaslavskiy and Jordi Abante and Abecassis, {Barbara Schmitz} and Nanne Aben and Delasa Aghamirzaie and Tero Aittokallio and Akhtari, {Farida S.} and Bissan Al-lazikani and Tanvir Alam and Amin Allam and Chad Allen and {de Almeida}, {Mariana Pelicano} and Doaa Altarawy and Vinicius Alves and Alicia Amadoz and Benedict Anchang and Antolin, {Albert A.} and Ash, {Jeremy R.} and Aznar, {Victoria Romeo} and Wail Ba-alawi and Moeen Bagheri and Vladimir Bajic and Gordon Ball and Ballester, {Pedro J.} and Delora Baptista and Christopher Bare and Mathilde Bateson and Andreas Bender and Denis Bertrand and Bhagya Wijayawardena and Boroevich, {Keith A.} and Evert Bosdriesz and Salim Bougouffa and Gergana Bounova and Thomas Brouwer and Barbara Bryant and Manuel Calaza and Alberto Calderone and Stefano Calza and Stephen Capuzzi and Jose Carbonell-Caballero and Daniel Carlin and Hannah Carter and Luisa Castagnoli and Remzi Celebi and Gianni Cesareni and Hyeokyoon Chang and Guocai Chen and Haoran Chen and Huiyuan Chen and Lijun Cheng and Ariel Chernomoretz and Davide Chicco and Cho, {Kwang Hyun} and Sunghwan Cho and Daeseon Choi and Jaejoon Choi and Kwanghun Choi and Minsoo Choi and Cock, {Martine De} and Elizabeth Coker and Isidro Cortes-Ciriano and Mikl{\'o}s Cserz{\"o} and Cankut Cubuk and Christina Curtis and Daele, {Dries Van} and Dang, {Cuong C.} and Tjeerd Dijkstra and Joaquin Dopazo and Sorin Draghici and Anastasios Drosou and Michel Dumontier and Friederike Ehrhart and Eid, {Fatma Elzahraa} and Mahmoud ElHefnawi and Haitham Elmarakeby and {van Engelen}, Bo and Engin, {Hatice Billur} and {de Esch}, Iwan and Chris Evelo and Falcao, {Andre O.} and Sherif Farag and Carlos Fernandez-Lozano and Kathleen Fisch and Asmund Flobak and Chiara Fornari and Foroushani, {Amir B.K.} and Fotso, {Donatien Chedom} and Denis Fourches and Stephen Friend and Arnoldo Frigessi and Feng Gao and Xiaoting Gao and Gerold, {Jeffrey M.} and Pierre Gestraud and Samik Ghosh and Jussi Gillberg and Antonia Godoy-Lorite and Lizzy Godynyuk and Adam Godzik and Anna Goldenberg and David Gomez-Cabrero and Mehmet Gonen and {de Graaf}, Chris and Harry Gray and Maxim Grechkin and Roger Guimera and Emre Guney and Benjamin Haibe-Kains and Younghyun Han and Takeshi Hase and Di He and Liye He and Heath, {Lenwood S.} and Hellton, {Kristoffer H.} and Manuela Helmer-Citterich and Hidalgo, {Marta R.} and Daniel Hidru and Hill, {Steven M.} and Sepp Hochreiter and Seungpyo Hong and Eivind Hovig and Hsueh, {Ya Chih} and Zhiyuan Hu and Huang, {Justin K.} and Huang, {R. Stephanie} and L{\'a}szl{\'o} Hunyady and Jinseub Hwang and Hwang, {Tae Hyun} and Woochang Hwang and Yongdeuk Hwang and Olexandr Isayev and {Don{\textquoteright}t Walk}, {Oliver Bear} and John Jack and Samad Jahandideh and Jiadong Ji and Yousang Jo and Kamola, {Piotr J.} and Kanev, {Georgi K.} and Loukia Karacosta and Mostafa Karimi and Samuel Kaski and Marat Kazanov and Khamis, {Abdullah M.} and Khan, {Suleiman Ali} and Kiani, {Narsis A.} and Allen Kim and Jinhan Kim and Juntae Kim and Kiseong Kim and Kyung Kim and Sunkyu Kim and Yongsoo Kim and Yunseong Kim and Kirk, {Paul D.W.} and Hiroaki Kitano and Gunter Klambauer and David Knowles and Melissa Ko and Alvaro Kohn-Luque and Kooistra, {Albert J.} and Kuenemann, {Melaine A.} and Martin Kuiper and Christoph Kurz and Mijin Kwon and {van Laarhoven}, Twan and Astrid Laegreid and Simone Lederer and Heewon Lee and Jeon Lee and Lee, {Yun Woo} and Eemeli Lepp_aho and Richard Lewis and Jing Li and Lang Li and James Liley and Lim, {Weng Khong} and Chieh Lin and Yiyi Liu and Yosvany Lopez and Joshua Low and Artem Lysenko and Daniel Machado and Neel Madhukar and Maeyer, {Dries De} and Malpartida, {Ana Belen} and Hiroshi Mamitsuka and Francesco Marabita and Kathleen Marchal and Pekka Marttinen and Daniel Mason and Alireza Mazaheri and Arfa Mehmood and Ali Mehreen and Magali Michaut and Miller, {Ryan A.} and Costas Mitsopoulos and Dezso Modos and Moerbeke, {Marijke Van} and Keagan Moo and Alison Motsinger-Reif and Rajiv Movva and Sebastian Muraru and Eugene Muratov and Mushthofa Mushthofa and Niranjan Nagarajan and Sigve Nakken and Aritro Nath and Pierre Neuvial and Richard Newton and Zheng Ning and Niz, {Carlos De} and Baldo Oliva and Catharina Olsen and Antonio Palmeri and Bhawan Panesar and Stavros Papadopoulos and Jaesub Park and Seonyeong Park and Sungjoon Park and Yudi Pawitan and Daniele Peluso and Sriram Pendyala and Jian Peng and Livia Perfetto and Stefano Pirro and Sylvia Plevritis and Regina Politi and Hoifung Poon and Eduard Porta and Isak Prellner and Kristina Preuer and Pujana, {Miguel Angel} and Ricardo Ramnarine and Reid, {John E.} and Fabien Reyal and Sylvia Richardson and Camir Ricketts and Linda Rieswijk and Miguel Rocha and Carmen Rodriguez-Gonzalvez and Kyle Roell and Daniel Rotroff and {de Ruiter}, {Julian R.} and Ploy Rukawa and Benjamin Sadacca and Zhaleh Safikhani and Fita Safitri and Marta Sales-Pardo and Sebastian Sauer and Moritz Schlichting and Seoane, {Jose A.} and Jordi Serra and Shang, {Ming Mei} and Alok Sharma and Hari Sharma and Yang Shen and Motoki Shiga and Moonshik Shin and Ziv Shkedy and Kevin Shopsowitz and Sam Sinai and Dylan Skola and Petr Smirnov and Soerensen, {Izel Fourie} and Peter Soerensen and Song, {Je Hoon} and Song, {Sang Ok} and Othman Soufan and Andreas Spitzmueller and Boris Steipe and Chayaporn Suphavilai and Tamayo, {Sergio Pulido} and David Tamborero and Jing Tang and Tanoli, {Zia ur Rehman} and Marc Tarres-Deulofeu and Jesper Tegner and Liv Thommesen and Tonekaboni, {Seyed Ali Madani} and Hong Tran and Troyer, {Ewoud De} and Amy Truong and Tatsuhiko Tsunoda and G{\'a}bor Turu and Tzeng, {Guang Yo} and Lieven Verbeke and Santiago Videla and Daniel Vis and Andrey Voronkov and Konstantinos Votis and Ashley Wang and Wang, {Hong Qiang Horace} and Wang, {Po Wei} and Sheng Wang and Wei Wang and Xiaochen Wang and Xin Wang and Krister Wennerberg and Lorenz Wernisch and Lodewyk Wessels and {van Westen}, {Gerard J.P.} and Westerman, {Bart A.} and White, {Simon Richard} and Egon Willighagen and Tom Wurdinger and Lei Xie and Shuilian Xie and Hua Xu and Bhagwan Yadav and Christopher Yau and Huwate Yeerna and Yin, {Jia Wei} and Michael Yu and Yu, {Min Hwan} and Yun, {So Jeong} and Alexey Zakharov and Alexandros Zamichos and Massimiliano Zanin and Li Zeng and Hector Zenil and Frederick Zhang and Pengyue Zhang and Wei Zhang and Hongyu Zhao and Lan Zhao and Wenjin Zheng and Azedine Zoufir and Manuela Zucknick and Jang, {In Sock} and Zara Ghazoui and Ahsen, {Mehmet Eren} and Robert Vogel and Neto, {Elias Chaibub} and Thea Norman and Tang, {Eric K.Y.} and Garnett, {Mathew J.} and Veroli, {Giovanni Y.Di} and Stephen Fawell and Gustavo Stolovitzky and Justin Guinney and Dry, {Jonathan R.} and Julio Saez-Rodriguez and {AstraZeneca-Sanger Drug Combination DREAM Consortium}",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-09799-2",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

AU - Menden, Michael P.

AU - Wang, Dennis

AU - Mason, Mike J.

AU - Szalai, Bence

AU - Bulusu, Krishna C.

AU - Guan, Yuanfang

AU - Yu, Thomas

AU - Kang, Jaewoo

AU - Jeon, Minji

AU - Wolfinger, Russ

AU - Nguyen, Tin

AU - Zaslavskiy, Mikhail

AU - Abante, Jordi

AU - Abecassis, Barbara Schmitz

AU - Aben, Nanne

AU - Aghamirzaie, Delasa

AU - Aittokallio, Tero

AU - Akhtari, Farida S.

AU - Al-lazikani, Bissan

AU - Alam, Tanvir

AU - Allam, Amin

AU - Allen, Chad

AU - de Almeida, Mariana Pelicano

AU - Altarawy, Doaa

AU - Alves, Vinicius

AU - Amadoz, Alicia

AU - Anchang, Benedict

AU - Antolin, Albert A.

AU - Ash, Jeremy R.

AU - Aznar, Victoria Romeo

AU - Ba-alawi, Wail

AU - Bagheri, Moeen

AU - Bajic, Vladimir

AU - Ball, Gordon

AU - Ballester, Pedro J.

AU - Baptista, Delora

AU - Bare, Christopher

AU - Bateson, Mathilde

AU - Bender, Andreas

AU - Bertrand, Denis

AU - Wijayawardena, Bhagya

AU - Boroevich, Keith A.

AU - Bosdriesz, Evert

AU - Bougouffa, Salim

AU - Bounova, Gergana

AU - Brouwer, Thomas

AU - Bryant, Barbara

AU - Calaza, Manuel

AU - Calderone, Alberto

AU - Calza, Stefano

AU - Capuzzi, Stephen

AU - Carbonell-Caballero, Jose

AU - Carlin, Daniel

AU - Carter, Hannah

AU - Castagnoli, Luisa

AU - Celebi, Remzi

AU - Cesareni, Gianni

AU - Chang, Hyeokyoon

AU - Chen, Guocai

AU - Chen, Haoran

AU - Chen, Huiyuan

AU - Cheng, Lijun

AU - Chernomoretz, Ariel

AU - Chicco, Davide

AU - Cho, Kwang Hyun

AU - Cho, Sunghwan

AU - Choi, Daeseon

AU - Choi, Jaejoon

AU - Choi, Kwanghun

AU - Choi, Minsoo

AU - Cock, Martine De

AU - Coker, Elizabeth

AU - Cortes-Ciriano, Isidro

AU - Cserzö, Miklós

AU - Cubuk, Cankut

AU - Curtis, Christina

AU - Daele, Dries Van

AU - Dang, Cuong C.

AU - Dijkstra, Tjeerd

AU - Dopazo, Joaquin

AU - Draghici, Sorin

AU - Drosou, Anastasios

AU - Dumontier, Michel

AU - Ehrhart, Friederike

AU - Eid, Fatma Elzahraa

AU - ElHefnawi, Mahmoud

AU - Elmarakeby, Haitham

AU - van Engelen, Bo

AU - Engin, Hatice Billur

AU - de Esch, Iwan

AU - Evelo, Chris

AU - Falcao, Andre O.

AU - Farag, Sherif

AU - Fernandez-Lozano, Carlos

AU - Fisch, Kathleen

AU - Flobak, Asmund

AU - Fornari, Chiara

AU - Foroushani, Amir B.K.

AU - Fotso, Donatien Chedom

AU - Fourches, Denis

AU - Friend, Stephen

AU - Frigessi, Arnoldo

AU - Gao, Feng

AU - Gao, Xiaoting

AU - Gerold, Jeffrey M.

AU - Gestraud, Pierre

AU - Ghosh, Samik

AU - Gillberg, Jussi

AU - Godoy-Lorite, Antonia

AU - Godynyuk, Lizzy

AU - Godzik, Adam

AU - Goldenberg, Anna

AU - Gomez-Cabrero, David

AU - Gonen, Mehmet

AU - de Graaf, Chris

AU - Gray, Harry

AU - Grechkin, Maxim

AU - Guimera, Roger

AU - Guney, Emre

AU - Haibe-Kains, Benjamin

AU - Han, Younghyun

AU - Hase, Takeshi

AU - He, Di

AU - He, Liye

AU - Heath, Lenwood S.

AU - Hellton, Kristoffer H.

AU - Helmer-Citterich, Manuela

AU - Hidalgo, Marta R.

AU - Hidru, Daniel

AU - Hill, Steven M.

AU - Hochreiter, Sepp

AU - Hong, Seungpyo

AU - Hovig, Eivind

AU - Hsueh, Ya Chih

AU - Hu, Zhiyuan

AU - Huang, Justin K.

AU - Huang, R. Stephanie

AU - Hunyady, László

AU - Hwang, Jinseub

AU - Hwang, Tae Hyun

AU - Hwang, Woochang

AU - Hwang, Yongdeuk

AU - Isayev, Olexandr

AU - Don’t Walk, Oliver Bear

AU - Jack, John

AU - Jahandideh, Samad

AU - Ji, Jiadong

AU - Jo, Yousang

AU - Kamola, Piotr J.

AU - Kanev, Georgi K.

AU - Karacosta, Loukia

AU - Karimi, Mostafa

AU - Kaski, Samuel

AU - Kazanov, Marat

AU - Khamis, Abdullah M.

AU - Khan, Suleiman Ali

AU - Kiani, Narsis A.

AU - Kim, Allen

AU - Kim, Jinhan

AU - Kim, Juntae

AU - Kim, Kiseong

AU - Kim, Kyung

AU - Kim, Sunkyu

AU - Kim, Yongsoo

AU - Kim, Yunseong

AU - Kirk, Paul D.W.

AU - Kitano, Hiroaki

AU - Klambauer, Gunter

AU - Knowles, David

AU - Ko, Melissa

AU - Kohn-Luque, Alvaro

AU - Kooistra, Albert J.

AU - Kuenemann, Melaine A.

AU - Kuiper, Martin

AU - Kurz, Christoph

AU - Kwon, Mijin

AU - van Laarhoven, Twan

AU - Laegreid, Astrid

AU - Lederer, Simone

AU - Lee, Heewon

AU - Lee, Jeon

AU - Lee, Yun Woo

AU - Lepp_aho, Eemeli

AU - Lewis, Richard

AU - Li, Jing

AU - Li, Lang

AU - Liley, James

AU - Lim, Weng Khong

AU - Lin, Chieh

AU - Liu, Yiyi

AU - Lopez, Yosvany

AU - Low, Joshua

AU - Lysenko, Artem

AU - Machado, Daniel

AU - Madhukar, Neel

AU - Maeyer, Dries De

AU - Malpartida, Ana Belen

AU - Mamitsuka, Hiroshi

AU - Marabita, Francesco

AU - Marchal, Kathleen

AU - Marttinen, Pekka

AU - Mason, Daniel

AU - Mazaheri, Alireza

AU - Mehmood, Arfa

AU - Mehreen, Ali

AU - Michaut, Magali

AU - Miller, Ryan A.

AU - Mitsopoulos, Costas

AU - Modos, Dezso

AU - Moerbeke, Marijke Van

AU - Moo, Keagan

AU - Motsinger-Reif, Alison

AU - Movva, Rajiv

AU - Muraru, Sebastian

AU - Muratov, Eugene

AU - Mushthofa, Mushthofa

AU - Nagarajan, Niranjan

AU - Nakken, Sigve

AU - Nath, Aritro

AU - Neuvial, Pierre

AU - Newton, Richard

AU - Ning, Zheng

AU - Niz, Carlos De

AU - Oliva, Baldo

AU - Olsen, Catharina

AU - Palmeri, Antonio

AU - Panesar, Bhawan

AU - Papadopoulos, Stavros

AU - Park, Jaesub

AU - Park, Seonyeong

AU - Park, Sungjoon

AU - Pawitan, Yudi

AU - Peluso, Daniele

AU - Pendyala, Sriram

AU - Peng, Jian

AU - Perfetto, Livia

AU - Pirro, Stefano

AU - Plevritis, Sylvia

AU - Politi, Regina

AU - Poon, Hoifung

AU - Porta, Eduard

AU - Prellner, Isak

AU - Preuer, Kristina

AU - Pujana, Miguel Angel

AU - Ramnarine, Ricardo

AU - Reid, John E.

AU - Reyal, Fabien

AU - Richardson, Sylvia

AU - Ricketts, Camir

AU - Rieswijk, Linda

AU - Rocha, Miguel

AU - Rodriguez-Gonzalvez, Carmen

AU - Roell, Kyle

AU - Rotroff, Daniel

AU - de Ruiter, Julian R.

AU - Rukawa, Ploy

AU - Sadacca, Benjamin

AU - Safikhani, Zhaleh

AU - Safitri, Fita

AU - Sales-Pardo, Marta

AU - Sauer, Sebastian

AU - Schlichting, Moritz

AU - Seoane, Jose A.

AU - Serra, Jordi

AU - Shang, Ming Mei

AU - Sharma, Alok

AU - Sharma, Hari

AU - Shen, Yang

AU - Shiga, Motoki

AU - Shin, Moonshik

AU - Shkedy, Ziv

AU - Shopsowitz, Kevin

AU - Sinai, Sam

AU - Skola, Dylan

AU - Smirnov, Petr

AU - Soerensen, Izel Fourie

AU - Soerensen, Peter

AU - Song, Je Hoon

AU - Song, Sang Ok

AU - Soufan, Othman

AU - Spitzmueller, Andreas

AU - Steipe, Boris

AU - Suphavilai, Chayaporn

AU - Tamayo, Sergio Pulido

AU - Tamborero, David

AU - Tang, Jing

AU - Tanoli, Zia ur Rehman

AU - Tarres-Deulofeu, Marc

AU - Tegner, Jesper

AU - Thommesen, Liv

AU - Tonekaboni, Seyed Ali Madani

AU - Tran, Hong

AU - Troyer, Ewoud De

AU - Truong, Amy

AU - Tsunoda, Tatsuhiko

AU - Turu, Gábor

AU - Tzeng, Guang Yo

AU - Verbeke, Lieven

AU - Videla, Santiago

AU - Vis, Daniel

AU - Voronkov, Andrey

AU - Votis, Konstantinos

AU - Wang, Ashley

AU - Wang, Hong Qiang Horace

AU - Wang, Po Wei

AU - Wang, Sheng

AU - Wang, Wei

AU - Wang, Xiaochen

AU - Wang, Xin

AU - Wennerberg, Krister

AU - Wernisch, Lorenz

AU - Wessels, Lodewyk

AU - van Westen, Gerard J.P.

AU - Westerman, Bart A.

AU - White, Simon Richard

AU - Willighagen, Egon

AU - Wurdinger, Tom

AU - Xie, Lei

AU - Xie, Shuilian

AU - Xu, Hua

AU - Yadav, Bhagwan

AU - Yau, Christopher

AU - Yeerna, Huwate

AU - Yin, Jia Wei

AU - Yu, Michael

AU - Yu, Min Hwan

AU - Yun, So Jeong

AU - Zakharov, Alexey

AU - Zamichos, Alexandros

AU - Zanin, Massimiliano

AU - Zeng, Li

AU - Zenil, Hector

AU - Zhang, Frederick

AU - Zhang, Pengyue

AU - Zhang, Wei

AU - Zhao, Hongyu

AU - Zhao, Lan

AU - Zheng, Wenjin

AU - Zoufir, Azedine

AU - Zucknick, Manuela

AU - Jang, In Sock

AU - Ghazoui, Zara

AU - Ahsen, Mehmet Eren

AU - Vogel, Robert

AU - Neto, Elias Chaibub

AU - Norman, Thea

AU - Tang, Eric K.Y.

AU - Garnett, Mathew J.

AU - Veroli, Giovanni Y.Di

AU - Fawell, Stephen

AU - Stolovitzky, Gustavo

AU - Guinney, Justin

AU - Dry, Jonathan R.

AU - Saez-Rodriguez, Julio

AU - AstraZeneca-Sanger Drug Combination DREAM Consortium

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85067453487&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067453487&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-09799-2

DO - 10.1038/s41467-019-09799-2

M3 - Article

C2 - 31209238

AN - SCOPUS:85067453487

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2674

ER -

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

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