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.

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen / Menden, Mp; Wang, D; Mason, Mj; Szalai, B; Bulusu, Kc; Guan, Yf; Yu, T; Kang, J; Jeon, M; Wolfinger, R; Nguyen, T; Zaslavskiy, M; Jang, Is; Ghazoui, Z; Ahsen, Me; Vogel, R; Neto, Ec; Norman, T; Tang, Eky; Garnett, Mj; Di Veroli, Gy; Fawell, S; Stolovitzky, G; Guinney, J; Dry, Jr; Saez-Rodriguez, J; Abante, J; Abecassis, Bs; Aben, N; Aghamirzaie, D; Aittokallio, T; Akhtari, Fs; Al-lazikani, B; Alam, T; Allam, A; Allen, C; de Almeida, Mp; Altarawy, D; Alves, V; Amadoz, A; Anchang, B; Antolin, Aa; Ash, Jr; Aznar, Vr; Ba-alawi, W; Bagheri, M; Bajic, V; Ball, G; Ballester, Pj; Baptista, D; Bare, C; Bateson, M; Bender, A; Bertrand, D; Wijayawardena, B; Boroevich, Ka; Bosdriesz, E; Bougouffa, S; Bounova, G; Brouwer, T; Bryant, B; Calaza, M; Calderone, A; Calza, S; Capuzzi, S; Carbonell-Caballero, J; Carlin, D; Carter, H; Castagnoli, L; Celebi, R; Cesareni, G; Chang, H; Chen, Gc; Chen, Hr; Chen, Hy; Cheng, Lj; Chernomoretz, A; Chicco, D; Cho, Kh; Cho, S; Choi, D; Choi, J; Choi, K; Choi, M; De Cock, M; Coker, E; Cortes-Ciriano, I; Cserzo, M; Cubuk, C; Curtis, C; Van Daele, D; Dang, Cc; Dijkstra, T; Dopazo, J; Draghici, S; Drosou, A; Dumontier, M; Ehrhart, F; Eid, Fe; Elhefnawi, M; Elmarakeby, H; van Engelen, B; Engin, Hb; de Esch, I; Evelo, C; Falcao, Ao; Farag, S; Fernandez-Lozano, C; Fisch, K; Flobak, A; Fornari, C; Foroushani, Abk; Fotso, Dc; Fourches, D; Friend, S; Frigessi, A; Gao, F; Gao, Xt; Gerold, Jm; Gestraud, P; Ghosh, S; Gillberg, J; Godoy-Lorite, A; Godynyuk, L; Godzik, A; Goldenberg, A; Gomez-Cabrero, D; Gonen, M; de Graaf, C; Gray, H; Grechkin, M; Guimera, R; Guney, E; Haibe-Kains, B; Han, Y; Hase, T; He, D; He, Ly; Heath, Ls; Hellton, Kh; Helmer-Citterich, M; Hidalgo, Mr; Hidru, D; Hill, Sm; Hochreiter, S; Hong, S; Hovig, E; Hsueh, Yc; Hu, Zy; Huang, Jk; Huang, Rs; Hunyady, L; Hwang, J; Hwang, Th; Hwang, W; Hwang, Y; Isayev, O; Walk, Obd; Jack, J; Jahandideh, S; Ji, Jd; Jo, Y; Kamola, Pj; Kanev, Gk; Karacosta, L; Karimi, M; Kaski, S; Kazanov, M; Khamis, Am; Khan, Sa; Kiani, Na; Kim, A; Kim, J; Kim, J; Kim, K; Kim, K; Kim, S; Kim, Y; Kim, Y; Kirk, Pdw; Kitano, H; Klambauer, G; Knowles, D; Ko, M; Kohn-Luque, A; Kooistra, Aj; Kuenemann, Ma; Kuiper, M; Kurz, C; Kwon, M; van Laarhoven, T; Laegreid, A; Lederer, S; Lee, H; Lee, J; Lee, Yw; Leppaho, E; Lewis, R; Li, J; Li, L; Liley, J; Lim, Wk; Lin, C; Liu, Yy; Lopez, Y; Low, J; Lysenko, A; Machado, D; Madhukar, N; De Maeyer, D; Malpartida, Ab; Mamitsuka, H; Marabita, F; Marchal, K; Marttinen, P; Mason, D; Mazaheri, A; Mehmood, A; Mehreen, A; Michaut, M; Miller, Ra; Mitsopoulos, C; Modos, D; Van Moerbeke, M; Moo, K; Motsinger-Reif, A; Movva, R; Muraru, S; Muratov, E; Mushthofa, M; Nagarajan, N; Nakken, S; Nath, A; Neuvial, P; Newton, R; Ning, Z; De Niz, C; Oliva, B; Olsen, C; Palmeri, A; Panesar, B; Papadopoulos, S; Park, J; Park, S; Park, S; Pawitan, Y; Peluso, D; Pendyala, S; Peng, J; Perfetto, L; Pirro, S; Plevritis, S; Politi, R; Poon, H; Porta, E; Prellner, I; Preuer, K; Pujana, Ma; Ramnarine, R; Reid, Je; Reyal, F; Richardson, S; Ricketts, C; Rieswijk, L; Rocha, M; Rodriguez-Gonzalvez, C; Roell, K; Rotroff, D; de Ruiter, Jr; Rukawa, P; Sadacca, B; Safikhani, Z; Safitri, F; Sales-Pardo, M; Sauer, S; Schlichting, M; Seoane, Ja; Serra, J; Shang, Mm; Sharma, A; Sharma, H; Shen, Y; Shiga, M; Shin, M; Shkedy, Z; Shopsowitz, K; Sinai, S; Skola, D; Smirnov, P; Soerensen, If; Soerensen, P; Song, Jh; Song, So; Soufan, O; Spitzmueller, A; Steipe, B; Suphavilai, C; Tamayo, Sp; Tamborero, D; Tang, J; Tanoli, Zur; Tarres-Deulofeu, M; Tegner, J; Thommesen, L; Tonekaboni, Sam; Tran, H; De Troyer, E; Truong, A; Tsunoda, T; Turu, G; Tzeng, Gy; Verbeke, L; Videla, S; Vis, D; Voronkov, A; Votis, K; Wang, A; Wang, Hqh; Wang, Pw; Wang, S; Wang, W; Wang, Xc; Wang, X; Wennerberg, K; Wernisch, L; Wessels, L; van Westen, Gjp; Westerman, Ba; White, Sr; Willighagen, E; Wurdinger, T; Xie, L; Xie, Sl; Xu, H; Yadav, B; Yau, C; Yeerna, H; Yin, Jw; Yu, M; Yu, M; Yun, Sj; Zakharov, A; Zamichos, A; Zanin, M; Zeng, L; Zenil, H; Zhang, F; Zhang, Py; Zhang, W; Zhao, Hy; Zhao, L; Zheng, Wj; Zoufir, A; Zucknick, M. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019). [10.1038/s41467-019-09799-2]

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

Perfetto L;
2019

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.
2019
Cancer; Drug combinations; Machine Learning; predictions
01 Pubblicazione su rivista::01a Articolo in rivista
Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen / Menden, Mp; Wang, D; Mason, Mj; Szalai, B; Bulusu, Kc; Guan, Yf; Yu, T; Kang, J; Jeon, M; Wolfinger, R; Nguyen, T; Zaslavskiy, M; Jang, Is; Ghazoui, Z; Ahsen, Me; Vogel, R; Neto, Ec; Norman, T; Tang, Eky; Garnett, Mj; Di Veroli, Gy; Fawell, S; Stolovitzky, G; Guinney, J; Dry, Jr; Saez-Rodriguez, J; Abante, J; Abecassis, Bs; Aben, N; Aghamirzaie, D; Aittokallio, T; Akhtari, Fs; Al-lazikani, B; Alam, T; Allam, A; Allen, C; de Almeida, Mp; Altarawy, D; Alves, V; Amadoz, A; Anchang, B; Antolin, Aa; Ash, Jr; Aznar, Vr; Ba-alawi, W; Bagheri, M; Bajic, V; Ball, G; Ballester, Pj; Baptista, D; Bare, C; Bateson, M; Bender, A; Bertrand, D; Wijayawardena, B; Boroevich, Ka; Bosdriesz, E; Bougouffa, S; Bounova, G; Brouwer, T; Bryant, B; Calaza, M; Calderone, A; Calza, S; Capuzzi, S; Carbonell-Caballero, J; Carlin, D; Carter, H; Castagnoli, L; Celebi, R; Cesareni, G; Chang, H; Chen, Gc; Chen, Hr; Chen, Hy; Cheng, Lj; Chernomoretz, A; Chicco, D; Cho, Kh; Cho, S; Choi, D; Choi, J; Choi, K; Choi, M; De Cock, M; Coker, E; Cortes-Ciriano, I; Cserzo, M; Cubuk, C; Curtis, C; Van Daele, D; Dang, Cc; Dijkstra, T; Dopazo, J; Draghici, S; Drosou, A; Dumontier, M; Ehrhart, F; Eid, Fe; Elhefnawi, M; Elmarakeby, H; van Engelen, B; Engin, Hb; de Esch, I; Evelo, C; Falcao, Ao; Farag, S; Fernandez-Lozano, C; Fisch, K; Flobak, A; Fornari, C; Foroushani, Abk; Fotso, Dc; Fourches, D; Friend, S; Frigessi, A; Gao, F; Gao, Xt; Gerold, Jm; Gestraud, P; Ghosh, S; Gillberg, J; Godoy-Lorite, A; Godynyuk, L; Godzik, A; Goldenberg, A; Gomez-Cabrero, D; Gonen, M; de Graaf, C; Gray, H; Grechkin, M; Guimera, R; Guney, E; Haibe-Kains, B; Han, Y; Hase, T; He, D; He, Ly; Heath, Ls; Hellton, Kh; Helmer-Citterich, M; Hidalgo, Mr; Hidru, D; Hill, Sm; Hochreiter, S; Hong, S; Hovig, E; Hsueh, Yc; Hu, Zy; Huang, Jk; Huang, Rs; Hunyady, L; Hwang, J; Hwang, Th; Hwang, W; Hwang, Y; Isayev, O; Walk, Obd; Jack, J; Jahandideh, S; Ji, Jd; Jo, Y; Kamola, Pj; Kanev, Gk; Karacosta, L; Karimi, M; Kaski, S; Kazanov, M; Khamis, Am; Khan, Sa; Kiani, Na; Kim, A; Kim, J; Kim, J; Kim, K; Kim, K; Kim, S; Kim, Y; Kim, Y; Kirk, Pdw; Kitano, H; Klambauer, G; Knowles, D; Ko, M; Kohn-Luque, A; Kooistra, Aj; Kuenemann, Ma; Kuiper, M; Kurz, C; Kwon, M; van Laarhoven, T; Laegreid, A; Lederer, S; Lee, H; Lee, J; Lee, Yw; Leppaho, E; Lewis, R; Li, J; Li, L; Liley, J; Lim, Wk; Lin, C; Liu, Yy; Lopez, Y; Low, J; Lysenko, A; Machado, D; Madhukar, N; De Maeyer, D; Malpartida, Ab; Mamitsuka, H; Marabita, F; Marchal, K; Marttinen, P; Mason, D; Mazaheri, A; Mehmood, A; Mehreen, A; Michaut, M; Miller, Ra; Mitsopoulos, C; Modos, D; Van Moerbeke, M; Moo, K; Motsinger-Reif, A; Movva, R; Muraru, S; Muratov, E; Mushthofa, M; Nagarajan, N; Nakken, S; Nath, A; Neuvial, P; Newton, R; Ning, Z; De Niz, C; Oliva, B; Olsen, C; Palmeri, A; Panesar, B; Papadopoulos, S; Park, J; Park, S; Park, S; Pawitan, Y; Peluso, D; Pendyala, S; Peng, J; Perfetto, L; Pirro, S; Plevritis, S; Politi, R; Poon, H; Porta, E; Prellner, I; Preuer, K; Pujana, Ma; Ramnarine, R; Reid, Je; Reyal, F; Richardson, S; Ricketts, C; Rieswijk, L; Rocha, M; Rodriguez-Gonzalvez, C; Roell, K; Rotroff, D; de Ruiter, Jr; Rukawa, P; Sadacca, B; Safikhani, Z; Safitri, F; Sales-Pardo, M; Sauer, S; Schlichting, M; Seoane, Ja; Serra, J; Shang, Mm; Sharma, A; Sharma, H; Shen, Y; Shiga, M; Shin, M; Shkedy, Z; Shopsowitz, K; Sinai, S; Skola, D; Smirnov, P; Soerensen, If; Soerensen, P; Song, Jh; Song, So; Soufan, O; Spitzmueller, A; Steipe, B; Suphavilai, C; Tamayo, Sp; Tamborero, D; Tang, J; Tanoli, Zur; Tarres-Deulofeu, M; Tegner, J; Thommesen, L; Tonekaboni, Sam; Tran, H; De Troyer, E; Truong, A; Tsunoda, T; Turu, G; Tzeng, Gy; Verbeke, L; Videla, S; Vis, D; Voronkov, A; Votis, K; Wang, A; Wang, Hqh; Wang, Pw; Wang, S; Wang, W; Wang, Xc; Wang, X; Wennerberg, K; Wernisch, L; Wessels, L; van Westen, Gjp; Westerman, Ba; White, Sr; Willighagen, E; Wurdinger, T; Xie, L; Xie, Sl; Xu, H; Yadav, B; Yau, C; Yeerna, H; Yin, Jw; Yu, M; Yu, M; Yun, Sj; Zakharov, A; Zamichos, A; Zanin, M; Zeng, L; Zenil, H; Zhang, F; Zhang, Py; Zhang, W; Zhao, Hy; Zhao, L; Zheng, Wj; Zoufir, A; Zucknick, M. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019). [10.1038/s41467-019-09799-2]
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