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

作者：Michael P. Menden, Dennis Wang, Mike J. Mason, Bence Szalai, Krishna C. Bulusu, Yuanfang Guan, Thomas Yu, Jaewoo Kang, Minji Jeon, Russ Wolfinger, Tin Nguyen, Mikhail Zaslavskiy, Jordi Abante, Barbara Schmitz Abecassis, Nanne Aben, Delasa Aghamirzaie, Tero Aittokallio, Farida S. Akhtari, Bissan Al‐Lazikani, Tanvir Alam, Amin Allam, Chad H. G. Allen, Mariana Pelicano de Almeida, Doaa Altarawy, Vinícius M. Alves, Alicia Amadoz, Benedict Anchang, Albert A. Antolín, Jeremy R. Ash, V. Aznar, Wail Ba-Alawi, Moeen Bagheri, Vladimir B. Bajić, G. C. Ball, Pedro J. Ballester, Delora Baptista, Christopher Bare, Mathilde Bateson, Andreas Bender, Denis Bertrand, Bhagya K. Wijayawardena, Keith A. Boroevich, Evert Bosdriesz, Salim Bougouffa, Gergana Bounova, Thomas Brouwer, Barbara M. Bryant, Manuel Calaza, Alberto Calderone, Stefano Calza, Stephen J. Capuzzi, José Carbonell‐Caballero, Daniel Carlin, Hannah Carter, Luisa Castagnoli, Remzi Çelebi, Gianni Cesareni, Hyeokyoon Chang, Guocai Chen, Hao Chen, Huiyuan Chen, Lijun Cheng, Ariel Chernomoretz, Davide Chicco, Kwang‐Hyun Cho, Sung‐Hwan Cho, Daeseon Choi, Jaejoon Choi, Kwanghun Choi, Minsoo Choi, Martine De Cock, Elizabeth A. Coker, Isidro Cortés‐Ciriano, Miklós Cserző, Cankut Çubuk, Christina Curtis, Dries Van Daele, Cuong Cao Dang, Tjeerd M. H. Dijkstra, Joaquı́n Dopazo, Sorin Drăghici, Anastasios Drosou, Michel Dumontier, Friederike Ehrhart, Fatma-Elzahraa Eid, Mahmoud ElHefnawi, Haitham Elmarakeby, Bo van Engelen, H. Billur Engin, Iwan J. P. de Esch, Chris T. Evelo, André O. Falcão, Sherif S. Farag, Carlos Fernandez-Lozano, Kathleen M. Fisch, Åsmund Flobak, Chiara Fornari, Amir Foroushani, Donatien Chedom Fotso, Denis Fourches, Stephen Friend, Arnoldo Frigessi, Feng Gao, Xiaoting Gao, Jeffrey M. Gerold, Pierre Gestraud, Samik Ghosh, Jussi Gillberg, Antonia Godoy‐Lorite, Lizzy Godynyuk, Adam Godzik, Anna Goldenberg, David Gómez-Cabrero, Mehmet Gönen, Chris de Graaf, Harry Gray, Maxim Grechkin, Roger Guimerà, Emre Güney, Benjamin Haibe‐Kains, Young-Hyun Han, Takeshi Hase, Di He, Liye He, Lenwood S. Heath, Kristoffer H. Hellton, Manuela Helmer‐Citterich, Marta R. Hidalgo, Daniel Hidru, Steven M. Hill, Sepp Hochreiter, Seungpyo Hong, Eivind Hovig, Ya-Chih Hsueh, Zhiyuan Hu, Justin K. Huang, R. Stephanie Huang, László Hunyady, Jinseub Hwang, Tae Hyun Hwang, Woochang Hwang, Yongdeuk Hwang, Olexandr Isayev, Oliver Bear Don’t Walk, John Jack, Samad Jahandideh, Jiadong Ji, Yousang Jo, Piotr J. Kamola, Georgi K. Kanev, Loukia Georgiou Karacosta, Mostafa Karimi, Samuel Kaski, Marat D. Kazanov, Abdullah M. Khamis, Suleiman A. Khan, Narsis A. Kiani, Allen Kim, Jin-Han Kim, Juntae Kim, Kiseong Kim, Kyung‐Hee Kim, Sunkyu Kim, Yongsoo Kim, Yunseong Kim, Paul Kirk, Hiroaki Kitano, Günter Klambauer, David A. Knowles, Melissa E. Ko, Alvaro Köhn‐Luque, Albert J. Kooistra, Mélaine A. Kuenemann, Martin Kuiper, Christoph Kurz, Mijin Kwon, Twan van Laarhoven, Astrid Lægreid, Simone Lederer, Heewon Lee, Jeon Lee, Yun Woo Lee, Eemeli Lepp aho, Richard A. Lewis, Jing Li, Lang Li, James Liley, Weng Khong Lim, Chieh Hubert Lin, Yiyi Liu, Yosvany López, Joshua Low, Artem Lysenko, Daniel Machado, Neel S. Madhukar, Dries De Maeyer, Ana Belén Malpartida, Hiroshi Mamitsuka, Francesco Marabita, Kathleen Marchal, Pekka Marttinen, Daniel J. Mason, Alireza Mazaheri, Arfa Mehmood, Ali Mehreen, Magali Michaut, Ryan A. Miller, Costas Mitsopoulos, Dezső Módos, Marijke Van Moerbeke, Keagan Moo, Alison A. Motsinger‐Reif, Rajiv Movva, Sebastian Muraru, Eugene Muratov, Mushthofa Mushthofa, Niranjan Nagarajan, Sigve Nakken, Aritro Nath, Pierre Neuvial, Richard Newton, Ning Zheng, Carlos De Niz, Baldo Oliva, Catharina Olsen, Antonio Palmeri, Bhawan Panesar, Stavros Papadopoulos, Jaesub Park, Seonyeong Park, Sung‐Joon Park, Yudi Pawitan, Daniele Peluso, Sriram Pendyala, Jian Peng, Livia Perfetto, S Pirro, Sylvia K. Plevritis, Regina Politi, Hoifung Poon, Eduard Porta‐Pardo, Isak Prellner, Kristina Preuer, Miguel Ángel Pujana, Ricardo Ramnarine, John E. Reid, Fabien Reyal, Sylvia Richardson, Camir Ricketts, Linda Rieswijk, Miguel Rocha, Carmen Rodríguez‐Gonzálvez, Kyle R. Roell, Daniel M. Rotroff, Julian R. de Ruiter, Ploy Rukawa, Benjamin Sadacca, Zhaleh Safikhani, Fita Safitri, Marta Sales‐Pardo, Sebastian Sauer, Moritz Schlichting, José A. Seoane, Jordi Serra, Ming-Mei Shang, Alok Sharma, Hari M. Sharma, Yang Shen, M. Shiga, Moonshik Shin, Ziv Shkedy, Kevin E. Shopsowitz, Sam Sinai, Dylan Skola, Petr Smirnov, Izel Fourie Soerensen, Peter Borgen Soerensen, Je-Hoon Song, Sang Ok Song, Othman Soufan, Andreas Spitzmueller, Boris Steipe, Chayaporn Suphavilai, Sergio Pulido Tamayo, David Tamborero, Jing Tang, Ziaurrehman Tanoli, Marc Tarrés-Deulofeu, Jesper Tegnér, Liv Thommesen, Seyed Ali Madani Tonekaboni, Hong Tran, Ewoud De Troyer, Amy Truong, Tatsuhiko Tsunoda, Gábor Turu, Guang-Yo Tzeng, Lieven Verbeke, Santiago Videla, Daniël J. Vis, Andrey Voronkov, Konstantinos Votis, Ashley Wang, Hong-Qiang Horace Wang, Po-Wei Wang, Sheng Wang, Wei Wang, Xiaochen Wang, Xin Wang, Krister Wennerberg, Lorenz Wernisch, Lodewyk F.A. Wessels, Gerard J. P. van Westen, Bart A. Westerman, Simon R. White, Egon Willighagen, Tom Würdinger, Lei Xie, Shuilian Xie, Hua Xu, Bhagwan Yadav, Christopher Yau, Huwate Yeerna, Jia Wei Yin, Michael Yu, MinHwan Yu, So Jeong Yun, Alexey Zakharov, Alexandros Zamichos, Massimiliano Zanin, Li Zeng, Héctor Zenil, Frederick Zhang, Pengyue Zhang, Wei Zhang, Hongyu Zhao, Lan Zhao, W. Jim Zheng, Azedine Zoufir, Manuela Zucknick, In Sock Jang, Zara Ghazoui, Mehmet Eren Ahsen, Robert Vogel, Elias Chaibub Neto, Thea Norman, Eric Tang, Mathew J. Garnett, Giovanni Y. Di Veroli, Stephen E. Fawell, Gustavo Stolovitzky, Justin Guinney, Jonathan R. Dry, Julio Sáez-Rodríguez · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-09799-2 · 被引用次数：373 · 研究领域：Computational Drug Discovery Methods、Bioinformatics and Genomic Networks、Protein Degradation and Inhibitors

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.