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

Author

Menden M, Wang D, Mason M, Szalai B, Bulusu K, Guan Y, Yu T, Kang J, Jeon M, Wolfinger R, Nguyen T, Zaslavskiy M, Jang I, Ghazoui Z, Ahsen M, Vogel R, Neto E, Norman T, Tang E, Garnett M, Di Veroli G, Fawell S, Stolovitzky G, Guinney J, Dry J, Saez-Rodriguez J, Abante J, Abecassis B, Aben N, Aghamirzaie D, Aittokallio T, Akhtari F, Al-lazikani B, Alam T, Allam A, Allen C, de Almeida M, Altarawy D, Alves V, Amadoz A, Anchang B, Antolin A, Ash J, Aznar V, Ba-alawi W, Bagheri M, Bajic V, Ball G, Ballester P, Baptista D, Bare C, Bateson M, Bender A, Bertrand D, Wijayawardena B, Boroevich K, 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 G, Chen H, Cheng L, Chernomoretz A, Chicco D, Cho K, 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 C, Dijkstra T, Dopazo J, Draghici S, Drosou A, Dumontier M, Ehrhart F, Eid F, ElHefnawi M, Elmarakeby H, van Engelen B, Engin H, de Esch I, Evelo C, Falcao A, Farag S, Fernandez-Lozano C, Fisch K, Flobak A, Fornari C, Foroushani A, Fotso D, Fourches D, Friend S, Frigessi A, Gao F, Gao X, Gerold J, 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 L, Heath L, Hellton K, Helmer-Citterich M, Hidalgo M, Hidru D, Hill S, Hochreiter S, Hong S, Hovig E, Hsueh Y, Hu Z, Huang J, Huang R, Hunyady L, Hwang J, Hwang T, Hwang W, Hwang Y, Isayev O, Walk O, Jack J, Jahandideh S, Ji J, Jo Y, Kamola P, Kanev G, Karacosta L, Karimi M, Kaski S, Kazanov M, Khamis A, Khan S, Kiani N, Kim A, Kim J, Kim K, Kim S, Kim Y, Kirk P, Kitano H, Klambauer G, Knowles D, Ko M, Kohn-Luque A, Kooistra A, Kuenemann M, Kuiper M, Kurz C, Kwon M, van Laarhoven T, Laegreid A, Lederer S, Lee H, Lee J, Lee Y, Leppaho E, Lewis R, Li J, Li L, Liley J, Lim W, Lin C, Liu Y, Lopez Y, Low J, Lysenko A, Machado D, Madhukar N, De Maeyer D, Malpartida A, Mamitsuka H, Marabita F, Marchal K, Marttinen P, Mason D, Mazaheri A, Mehmood A, Mehreen A, Michaut M, Miller R, 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, 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 M, Ramnarine R, Reid J, Reyal F, Richardson S, Ricketts C, Rieswijk L, Rocha M, Rodriguez-Gonzalvez C, Roell K, Rotroff D, de Ruiter J, Rukawa P, Sadacca B, Safikhani Z, Safitri F, Sales-Pardo M, Sauer S, Schlichting M, Seoane J, Serra J, Shang M, Sharma A, Sharma H, Shen Y, Shiga M, Shin M, Shkedy Z, Shopsowitz K, Sinai S, Skola D, Smirnov P, Soerensen I, Soerensen P, Song J, Song S, Soufan O, Spitzmueller A, Steipe B, Suphavilai C, Tamayo S, Tamborero D, Tang J, Tanoli Z, Tarres-Deulofeu M, Tegner J, Thommesen L, Tonekaboni S, Tran H, De Troyer E, Truong A, Tsunoda T, Turu G, Tzeng G, Verbeke L, Videla S, Vis D, Voronkov A, Votis K, Wang A, Wang H, Wang P, Wang S, Wang W, Wang X, Wennerberg K, Wernisch L, Wessels L, van Westen G, Westerman B, White S, Willighagen E, Wurdinger T, Xie L, Xie S, Xu H, Yadav B, Yau C, Yeerna H, Yin J, Yu M, Yun S, Zakharov A, Zamichos A, Zanin M, Zeng L, Zenil H, Zhang F, Zhang P, Zhang W, Zhao H, Zhao L, Zheng W, Zoufir A, Zucknick M, AstraZeneca-Sanger Drug Combinatio, Ege Üniversitesi, Gönen, Mehmet (ORCID 0000-0002-2483-075X & YÖK ID 237468), Menden, Michael P., Wang, Dennis, Mason, Mike J., Szalai, Bence, Bulusu, Krishna C., Guan, Yuanfang, Yu, Thomas, Kang, Jaewoo, Jeon, Minji, Wolfinger, Russ, Nguyen, Tin, Zaslavskiy, Mikhail, Jang, In Sock, Ghazoui, Zara, Ahsen, Mehmet Eren, Vogel, Robert, Neto, Elias Chaibub, Norman, Thea, Tang, Eric K. Y., Garnett, Mathew J., Di Veroli, Giovanni Y., Fawell, Stephen, Stolovitzky, Gustavo, Guinney, Justin, Dry, Jonathan R., Saez-Rodriguez, Julio, Abante, Jordi, Abecassis, Barbara Schmitz, Aben, Nanne, Aghamirzaie, Delasa, Aittokallio, Tero, Akhtari, Farida S., Al-lazikani, Bissan, Alam, Tanvir, Allam, Amin, Allen, Chad, de Almeida, Mariana Pelicano, Altarawy, Doaa, Alves, Vinicius, Amadoz, Alicia, Anchang, Benedict, Antolin, Albert A., Ash, Jeremy R., Romeo Aznar, Victoria, Ba-alawi, Wail, Bagheri, Moeen, Bajic, Vladimir, Ball, Gordon, Ballester, Pedro J., Baptista, Delora, Bare, Christopher, Bateson, Mathilde, Bender, Andreas, Bertrand, Denis, Wijayawardena, Bhagya, Boroevich, Keith A., Bosdriesz, Evert, Bougouffa, Salim, Bounova, Gergana, Brouwer, Thomas, Bryant, Barbara, Calaza, Manuel, Calderone, Alberto, Calza, Stefano, Capuzzi, Stephen, Carbonell-Caballero, Jose, Carlin, Daniel, Carter, Hannah, Castagnoli, Luisa, Celebi, Remzi, Cesareni, Gianni, Chang, Hyeokyoon, Chen, Guocai, Chen, Haoran, Chen, Huiyuan, Cheng, Lijun, Chernomoretz, Ariel, Chicco, Davide, Cho, Kwang-Hyun, Cho, Sunghwan, Choi, Daeseon, Choi, Jaejoon, Choi, Kwanghun, Choi, Minsoo, De Cock, Martine, Coker, Elizabeth, Cortes-Ciriano, Isidro, Cserzo, Miklos, Cubuk, Cankut, Curtis, Christina, Van Daele, Dries, Dang, Cuong C., Dijkstra, Tjeerd, Dopazo, Joaquin, Draghici, Sorin, Drosou, Anastasios, Dumontier, Michel, Ehrhart, Friederike, Eid, Fatma-Elzahraa, ElHefnawi, Mahmoud, Elmarakeby, Haitham, van Engelen, Bo, Engin, Hatice Billur, de Esch, Iwan, Evelo, Chris, Falcao, Andre O., Farag, Sherif, Fernandez-Lozano, Carlos, Fisch, Kathleen, Flobak, Asmund, Fornari, Chiara, Foroushani, Amir B. K., Fotso, Donatien Chedom, Fourches, Denis, Friend, Stephen, Frigessi, Arnoldo, Gao, Feng, Gao, Xiaoting, Gerold, Jeffrey M., Gestraud, Pierre, Ghosh, Samik, Gillberg, Jussi, Godoy-Lorite, Antonia, Godynyuk, Lizzy, Godzik, Adam, Goldenberg, Anna, Gomez-Cabrero, David, de Graaf, Chris, Gray, Harry, Grechkin, Maxim, Guimera, Roger, Guney, Emre, Haibe-Kains, Benjamin, Han, Younghyun, Hase, Takeshi, He, Di, He, Liye, Heath, Lenwood S., Hellton, Kristoffer H., Helmer-Citterich, Manuela, Hidalgo, Marta R., Hidru, Daniel, Hill, Steven M., Hochreiter, Sepp, Hong, Seungpyo, Hovig, Eivind, Hsueh, Ya-Chih, Hu, Zhiyuan, Huang, Justin K., Huang, R. Stephanie, Hunyady, Laszlo, Hwang, Jinseub, Hwang, Tae Hyun, Hwang, Woochang, Hwang, Yongdeuk, Isayev, Olexandr, Walk, Oliver Bear Don't, Jack, John, Jahandideh, Samad, Ji, Jiadong, Jo, Yousang, Kamola, Piotr J., Kanev, Georgi K., Karacosta, Loukia, Karimi, Mostafa, Kaski, Samuel, Kazanov, Marat, Khamis, Abdullah M., Khan, Suleiman Ali, Kiani, Narsis A., Kim, Allen, Kim, Jinhan, Kim, Juntae, Kim, Kiseong, Kim, Kyung, Kim, Sunkyu, Kim, Yongsoo, Kim, Yunseong, Kirk, Paul D. W., Kitano, Hiroaki, Klambauer, Gunter, Knowles, David, Ko, Melissa, Kohn-Luque, Alvaro, Kooistra, Albert J., Kuenemann, Melaine A., Kuiper, Martin, Kurz, Christoph, Kwon, Mijin, van Laarhoven, Twan, Laegreid, Astrid, Lederer, Simone, Lee, Heewon, Lee, Jeon, Lee, Yun Woo, Leppaho, Eemeli, Lewis, Richard, Li, Jing, Li, Lang, Liley, James, Lim, Weng Khong, Lin, Chieh, Liu, Yiyi, Lopez, Yosvany, Low, Joshua, Lysenko, Artem, Machado, Daniel, Madhukar, Neel, De Maeyer, Dries, Malpartida, Ana Belen, Mamitsuka, Hiroshi, Marabita, Francesco, Marchal, Kathleen, Marttinen, Pekka, Mason, Daniel, Mazaheri, Alireza, Mehmood, Arfa, Mehreen, Ali, Michaut, Magali, Miller, Ryan A., Mitsopoulos, Costas, Modos, Dezso, Van Moerbeke, Marijke, Moo, Keagan, Motsinger-Reif, Alison, Movva, Rajiv, Muraru, Sebastian, Muratov, Eugene, Mushthofa, Mushthofa, Nagarajan, Niranjan, Nakken, Sigve, Nath, Aritro, Neuvial, Pierre, Newton, Richard, Ning, Zheng, De Niz, Carlos, Oliva, Baldo, Olsen, Catharina, Palmeri, Antonio, Panesar, Bhawan, Papadopoulos, Stavros, Park, Jaesub, Park, Seonyeong, Park, Sungjoon, Pawitan, Yudi, Peluso, Daniele, Pendyala, Sriram, Peng, Jian, Perfetto, Livia, Pirro, Stefano, Plevritis, Sylvia, Politi, Regina, Poon, Hoifung, Porta, Eduard, Prellner, Isak, Preuer, Kristina, Angel Pujana, Miguel, Ramnarine, Ricardo, Reid, John E., Reyal, Fabien, Richardson, Sylvia, Ricketts, Camir, Rieswijk, Linda, Rocha, Miguel, Rodriguez-Gonzalvez, Carmen, Roell, Kyle, Rotroff, Daniel, de Ruiter, Julian R., Rukawa, Ploy, Sadacca, Benjamin, Safikhani, Zhaleh, Safitri, Fita, Sales-Pardo, Marta, Sauer, Sebastian, Schlichting, Moritz, Seoane, Jose A., Serra, Jordi, Shang, Ming-Mei, Sharma, Alok, Sharma, Hari, Shen, Yang, Shiga, Motoki, Shin, Moonshik, Shkedy, Ziv, Shopsowitz, Kevin, Sinai, Sam, Skola, Dylan, Smirnov, Petr, Soerensen, Izel Fourie, Soerensen, Peter, Song, Je-Hoon, Song, Sang Ok, Soufan, Othman, Spitzmueller, Andreas, Steipe, Boris, Suphavilai, Chayaporn, Tamayo, Sergio Pulido, Tamborero, David, Tang, Jing, Tanoli, Zia-ur-Rehman, Tarres-Deulofeu, Marc, Tegner, Jesper, Thommesen, Liv, Tonekaboni, Seyed Ali Madani, Tran, Hong, De Troyer, Ewoud, Truong, Amy, Tsunoda, Tatsuhiko, Turu, Gabor, Tzeng, Guang-Yo, Verbeke, Lieven, Videla, Santiago, Vis, Daniel, Voronkov, Andrey, Votis, Konstantinos, Wang, Ashley, Wang, Hong-Qiang Horace, Wang, Po-Wei, Wang, Sheng, Wang, Wei, Wang, Xiaochen, Wang, Xin, Wennerberg, Krister, Wernisch, Lorenz, Wessels, Lodewyk, van Westen, Gerard J. P., Westerman, Bart A., White, Simon Richard, Willighagen, Egon, Wurdinger, Tom, Xie, Lei, Xie, Shuilian, Xu, Hua, Yadav, Bhagwan, Yau, Christopher, Yeerna, Huwate, Yin, Jia Wei, Yu, Michael, Yu, MinHwan, Yun, So Jeong, Zakharov, Alexey, Zamichos, Alexandros, Zanin, Massimiliano, Zeng, Li, Zenil, Hector, Zhang, Frederick, Zhang, Pengyue, Zhang, Wei, Zhao, Hongyu, Zhao, Lan, Zheng, Wenjin, Zoufir, Azedine, Zucknick, Manuela, College of Engineering, Department of Industrial Engineering, Institute of Data Science, RS: FSE DACS IDS, Bioinformatica, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: FHML MaCSBio, Promovendi NTM, Tero Aittokallio / Principal Investigator, Bioinformatics, Institute for Molecular Medicine Finland, Hu, Z, Fotso, DC, Menden, M, Wang, D, Mason, M, Szalai, B, Bulusu, K, Guan, Y, Yu, T, Kang, J, Jeon, M, Wolfinger, R, Nguyen, T, Zaslavskiy, M, Abante, J, Abecassis, B, Aben, N, Aghamirzaie, D, Aittokallio, T, Akhtari, F, Al-lazikani, B, Alam, T, Allam, A, Allen, C, de Almeida, M, Altarawy, D, Alves, V, Amadoz, A, Anchang, B, Antolin, A, Ash, J, Aznar, V, Ba-alawi, W, Bagheri, M, Bajic, V, Ball, G, Ballester, P, Baptista, D, Bare, C, Bateson, M, Bender, A, Bertrand, D, Wijayawardena, B, Boroevich, K, 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, G, Chen, H, Cheng, L, Chernomoretz, A, Chicco, D, Cho, K, Cho, S, Choi, D, Choi, J, Choi, K, Choi, M, Cock, M, Coker, E, Cortes-Ciriano, I, Cserzo, M, Cubuk, C, Curtis, C, Daele, D, Dang, C, Dijkstra, T, Dopazo, J, Draghici, S, Drosou, A, Dumontier, M, Ehrhart, F, Eid, F, Elhefnawi, M, Elmarakeby, H, van Engelen, B, Engin, H, de Esch, I, Evelo, C, Falcao, A, Farag, S, Fernandez-Lozano, C, Fisch, K, Flobak, A, Fornari, C, Foroushani, A, Fotso, D, Fourches, D, Friend, S, Frigessi, A, Gao, F, Gao, X, Gerold, J, 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, L, Heath, L, Hellton, K, Helmer-Citterich, M, Hidalgo, M, Hidru, D, Hill, S, Hochreiter, S, Hong, S, Hovig, E, Hsueh, Y, Huang, J, Huang, R, Hunyady, L, Hwang, J, Hwang, T, Hwang, W, Hwang, Y, Isayev, O, Don't Walk, O, Jack, J, Jahandideh, S, Ji, J, Jo, Y, Kamola, P, Kanev, G, Karacosta, L, Karimi, M, Kaski, S, Kazanov, M, Khamis, A, Khan, S, Kiani, N, Kim, A, Kim, J, Kim, K, Kim, S, Kim, Y, Kirk, P, Kitano, H, Klambauer, G, Knowles, D, Ko, M, Kohn-Luque, A, Kooistra, A, Kuenemann, M, Kuiper, M, Kurz, C, Kwon, M, van Laarhoven, T, Laegreid, A, Lederer, S, Lee, H, Lee, J, Lee, Y, Lepp_aho, E, Lewis, R, Li, J, Li, L, Liley, J, Lim, W, Lin, C, Liu, Y, Lopez, Y, Low, J, Lysenko, A, Machado, D, Madhukar, N, Maeyer, D, Malpartida, A, Mamitsuka, H, Marabita, F, Marchal, K, Marttinen, P, Mason, D, Mazaheri, A, Mehmood, A, Mehreen, A, Michaut, M, Miller, R, Mitsopoulos, C, Modos, D, 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, Niz, C, Oliva, B, Olsen, C, Palmeri, A, Panesar, B, Papadopoulos, S, Park, J, 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, M, Ramnarine, R, Reid, J, Reyal, F, Richardson, S, Ricketts, C, Rieswijk, L, Rocha, M, Rodriguez-Gonzalvez, C, Roell, K, Rotroff, D, de Ruiter, J, Rukawa, P, Sadacca, B, Safikhani, Z, Safitri, F, Sales-Pardo, M, Sauer, S, Schlichting, M, Seoane, J, Serra, J, Shang, M, Sharma, A, Sharma, H, Shen, Y, Shiga, M, Shin, M, Shkedy, Z, Shopsowitz, K, Sinai, S, Skola, D, Smirnov, P, Soerensen, I, Soerensen, P, Song, J, Song, S, Soufan, O, Spitzmueller, A, Steipe, B, Suphavilai, C, Tamayo, S, Tamborero, D, Tang, J, Tanoli, Z, Tarres-Deulofeu, M, Tegner, J, Thommesen, L, Tonekaboni, S, Tran, H, Troyer, E, Truong, A, Tsunoda, T, Turu, G, Tzeng, G, Verbeke, L, Videla, S, Vis, D, Voronkov, A, Votis, K, Wang, A, Wang, H, Wang, P, Wang, S, Wang, W, Wang, X, Wennerberg, K, Wernisch, L, Wessels, L, van Westen, G, Westerman, B, White, S, Willighagen, E, Wurdinger, T, Xie, L, Xie, S, Xu, H, Yadav, B, Yau, C, Yeerna, H, Yin, J, Yu, M, Yun, S, Zakharov, A, Zamichos, A, Zanin, M, Zeng, L, Zenil, H, Zhang, F, Zhang, P, Zhang, W, Zhao, H, Zhao, L, Zheng, W, Zoufir, A, Zucknick, M, Jang, I, Ghazoui, Z, Ahsen, M, Vogel, R, Neto, E, Norman, T, Tang, E, Garnett, M, Veroli, G, Fawell, S, Stolovitzky, G, Guinney, J, Dry, J, Saez-Rodriguez, J, Menden, Michael P. [0000-0003-0267-5792], Mason, Mike J. [0000-0002-5652-7739], Yu, Thomas [0000-0002-5841-0198], Kang, Jaewoo [0000-0001-6798-9106], Nguyen, Tin [0000-0001-8001-9470], Ahsen, Mehmet Eren [0000-0002-4907-0427], Stolovitzky, Gustavo [0000-0002-9618-2819], Guinney, Justin [0000-0003-1477-1888], Saez-Rodriguez, Julio [0000-0002-8552-8976], Apollo - University of Cambridge Repository, Menden, Michael P [0000-0003-0267-5792], Mason, Mike J [0000-0002-5652-7739], Pathology, CCA - Cancer biology and immunology, Medical oncology laboratory, Neurosurgery, Chemistry and Pharmaceutical Sciences, AIMMS, Medicinal chemistry, Universidade do Minho, Department of Computer Science, Professorship Marttinen P., Aalto-yliopisto, and Aalto University

Subjects
Drug Resistance, 02 engineering and technology, 13, PATHWAY, Antineoplastic Combined Chemotherapy Protocols, Molecular Targeted Therapy, Càncer, lcsh:Science, media_common, Cancer, Tumor, Settore BIO/18, Settore BIO/11, Drug combinations, High-throughput screening, Drug Synergism, purl.org/becyt/ford/1.2 [https], Genomics, Machine Learning, predictions, 3. Good health, ddc, Technologie de l'environnement, contrôle de la pollution, Benchmarking, 5.1 Pharmaceuticals, Cancer treatment, Farmacogenètica, Science & Technology - Other Topics, Development of treatments and therapeutic interventions, 0210 nano-technology, Human, Drug, media_common.quotation_subject, Science, 49/23, ADAM17 Protein, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Machine learning, Genetics, Chimie, Humans, BREAST-CANCER, CELL, 49/98, Science & Technology, Antineoplastic Combined Chemotherapy Protocol, 45, MUTATIONS, Computational Biology, Androgen receptor, Breast-cancer, Gene, Cell, Inhibition, Resistance, Pathway, Mutations, Landscape, Resource, 631/114/1305, medicine.disease, Drug synergy, 49, 030104 developmental biology, Pharmacogenetics, Mutation, Ciências Médicas::Biotecnologia Médica, lcsh:Q, 631/154/1435/2163, Biomarkers, RESISTANCE, 0301 basic medicine, ING-INF/06 - BIOINGEGNERIA ELETTRONICA E INFORMATICA, Statistical methods, Computer science, General Physics and Astronomy, Datasets as Topic, Drug resistance, purl.org/becyt/ford/1 [https], Phosphatidylinositol 3-Kinases, Biotecnologia Médica [Ciências Médicas], Neoplasms, Science and technology, Phosphoinositide-3 Kinase Inhibitors, Multidisciplinary, Biomarkers, Tumor, Cell Line, Tumor, Drug Antagonism, Drug Resistance, Neoplasm, Treatment Outcome, Pharmacogenetic, article, ANDROGEN RECEPTOR, 49/39, 631/114/2415, 021001 nanoscience & nanotechnology, 692/4028/67, Multidisciplinary Sciences, 317 Pharmacy, Patient Safety, Systems biology, 3122 Cancers, INHIBITION, Computational biology, Cell Line, medicine, LANDSCAPE, Physique, Human Genome, Data Science, General Chemistry, AstraZeneca-Sanger Drug Combination DREAM Consortium, Astronomie, GENE, Good Health and Well Being, Pharmacogenomics, Genomic, Neoplasm, 631/553, Phosphatidylinositol 3-Kinase
Abstract

PubMed: 31209238, 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, The Author(s)., National Institute for Health Research, NIHR Wellcome Trust, WT: 102696, 206194 Magyar Tudományos Akadémia, MTA Bayer 668858 PrECISE AstraZeneca, We thank the Genomics of Drug Sensitivity in Cancer and COSMIC teams at the Wellcome Trust Sanger Institute for help with the preparation of the molecular data, Denes Turei for help with Omnipath, and Katjusa Koler for help with matching drug names across combination screens. We thank AstraZeneca for funding and provision of data to the DREAM Consortium to run the challenge, and funding from the European Union Horizon 2020 research (under grant agreement No 668858 PrECISE to J.S.R.), the Joint Research Center for Computational Biomedicine (which is partially funded by Bayer AG) to J.S.R., National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences. M.G lab is supported by Wellcome Trust (102696 and 206194)., Competing interests: K.C.B., Z.G., G.Y.D., E.K.Y.T., S.F., and J.R.D. are AstraZeneca employees. K.C.B., Z.G., E.K.Y.T., S.F., and J.R.D. are AstraZeneca shareholders. Y.G. receives personal compensation from Eli Lilly and Company, is a shareholder of Cleerly, Inc., and Ann Arbor Algorithms, Inc. M.G. receives research funding from AstraZeneca and has performed consultancy for Sanofi. The remaining authors declare no competing interests.

Published
2019

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

Author

Menden, M, Wang, D, Mason, M, Szalai, B, Bulusu, K, Guan, Y, Yu, T, Kang, J, Jeon, M, Wolfinger, R, Nguyen, T, Zaslavskiy, M, Abante, J, Abecassis, B, Aben, N, Aghamirzaie, D, Aittokallio, T, Akhtari, F, Al-lazikani, B, Alam, T, Allam, A, Allen, C, de Almeida, M, Altarawy, D, Alves, V, Amadoz, A, Anchang, B, Antolin, A, Ash, J, Aznar, V, Ba-alawi, W, Bagheri, M, Bajic, V, Ball, G, Ballester, P, Baptista, D, Bare, C, Bateson, M, Bender, A, Bertrand, D, Wijayawardena, B, Boroevich, K, 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, G, Chen, H, Cheng, L, Chernomoretz, A, Chicco, D, Cho, K, Cho, S, Choi, D, Choi, J, Choi, K, Choi, M, Cock, M, Coker, E, Cortes-Ciriano, I, Cserzo, M, Cubuk, C, Curtis, C, Daele, D, Dang, C, Dijkstra, T, Dopazo, J, Draghici, S, Drosou, A, Dumontier, M, Ehrhart, F, Eid, F, Elhefnawi, M, Elmarakeby, H, van Engelen, B, Engin, H, de Esch, I, Evelo, C, Falcao, A, Farag, S, Fernandez-Lozano, C, Fisch, K, Flobak, A, Fornari, C, Foroushani, A, Fotso, D, Fourches, D, Friend, S, Frigessi, A, Gao, F, Gao, X, Gerold, J, 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, L, Heath, L, Hellton, K, Helmer-Citterich, M, Hidalgo, M, Hidru, D, Hill, S, Hochreiter, S, Hong, S, Hovig, E, Hsueh, Y, Hu, Z, Huang, J, Huang, R, Hunyady, L, Hwang, J, Hwang, T, Hwang, W, Hwang, Y, Isayev, O, Don't Walk, O, Jack, J, Jahandideh, S, Ji, J, Jo, Y, Kamola, P, Kanev, G, Karacosta, L, Karimi, M, Kaski, S, Kazanov, M, Khamis, A, Khan, S, Kiani, N, Kim, A, Kim, J, Kim, K, Kim, S, Kim, Y, Kirk, P, Kitano, H, Klambauer, G, Knowles, D, Ko, M, Kohn-Luque, A, Kooistra, A, Kuenemann, M, Kuiper, M, Kurz, C, Kwon, M, van Laarhoven, T, Laegreid, A, Lederer, S, Lee, H, Lee, J, Lee, Y, Lepp_aho, E, Lewis, R, Li, J, Li, L, Liley, J, Lim, W, Lin, C, Liu, Y, Lopez, Y, Low, J, Lysenko, A, Machado, D, Madhukar, N, Maeyer, D, Malpartida, A, Mamitsuka, H, Marabita, F, Marchal, K, Marttinen, P, Mason, D, Mazaheri, A, Mehmood, A, Mehreen, A, Michaut, M, Miller, R, Mitsopoulos, C, Modos, D, 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, Niz, C, Oliva, B, Olsen, C, Palmeri, A, Panesar, B, Papadopoulos, S, Park, J, 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, M, Ramnarine, R, Reid, J, Reyal, F, Richardson, S, Ricketts, C, Rieswijk, L, Rocha, M, Rodriguez-Gonzalvez, C, Roell, K, Rotroff, D, de Ruiter, J, Rukawa, P, Sadacca, B, Safikhani, Z, Safitri, F, Sales-Pardo, M, Sauer, S, Schlichting, M, Seoane, J, Serra, J, Shang, M, Sharma, A, Sharma, H, Shen, Y, Shiga, M, Shin, M, Shkedy, Z, Shopsowitz, K, Sinai, S, Skola, D, Smirnov, P, Soerensen, I, Soerensen, P, Song, J, Song, S, Soufan, O, Spitzmueller, A, Steipe, B, Suphavilai, C, Tamayo, S, Tamborero, D, Tang, J, Tanoli, Z, Tarres-Deulofeu, M, Tegner, J, Thommesen, L, Tonekaboni, S, Tran, H, Troyer, E, Truong, A, Tsunoda, T, Turu, G, Tzeng, G, Verbeke, L, Videla, S, Vis, D, Voronkov, A, Votis, K, Wang, A, Wang, H, Wang, P, Wang, S, Wang, W, Wang, X, Wennerberg, K, Wernisch, L, Wessels, L, van Westen, G, Westerman, B, White, S, Willighagen, E, Wurdinger, T, Xie, L, Xie, S, Xu, H, Yadav, B, Yau, C, Yeerna, H, Yin, J, Yu, M, Yun, S, Zakharov, A, Zamichos, A, Zanin, M, Zeng, L, Zenil, H, Zhang, F, Zhang, P, Zhang, W, Zhao, H, Zhao, L, Zheng, W, Zoufir, A, Zucknick, M, Jang, I, Ghazoui, Z, Ahsen, M, Vogel, R, Neto, E, Norman, T, Tang, E, Garnett, M, Veroli, G, Fawell, S, Stolovitzky, G, Guinney, J, Dry, J, Saez-Rodriguez, J, Menden M. P., Wang D., Mason M. J., Szalai B., Bulusu K. C., Guan Y., Yu T., Kang J., Jeon M., Wolfinger R., Nguyen T., Zaslavskiy M., Abante J., Abecassis B. S., Aben N., Aghamirzaie D., Aittokallio T., Akhtari F. S., Al-lazikani B., Alam T., Allam A., Allen C., de Almeida M. P., Altarawy D., Alves V., Amadoz A., Anchang B., Antolin A. A., Ash J. R., Aznar V. R., Ba-alawi W., Bagheri M., Bajic V., Ball G., Ballester P. J., Baptista D., Bare C., Bateson M., Bender A., Bertrand D., Wijayawardena B., Boroevich K. A., 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 G., Chen H., Cheng L., Chernomoretz A., Chicco D., Cho K. -H., Cho S., Choi D., Choi J., Choi K., Choi M., Cock M. D., Coker E., Cortes-Ciriano I., Cserzo M., Cubuk C., Curtis C., Daele D. V., Dang C. C., Dijkstra T., Dopazo J., Draghici S., Drosou A., Dumontier M., Ehrhart F., Eid F. -E., ElHefnawi M., Elmarakeby H., van Engelen B., Engin H. B., de Esch I., Evelo C., Falcao A. O., Farag S., Fernandez-Lozano C., Fisch K., Flobak A., Fornari C., Foroushani A. B. K., Fotso D. C., Fourches D., Friend S., Frigessi A., Gao F., Gao X., Gerold J. M., 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 L., Heath L. S., Hellton K. H., Helmer-Citterich M., Hidalgo M. R., Hidru D., Hill S. M., Hochreiter S., Hong S., Hovig E., Hsueh Y. -C., Hu Z., Huang J. K., Huang R. S., Hunyady L., Hwang J., Hwang T. H., Hwang W., Hwang Y., Isayev O., Don't Walk O. B., Jack J., Jahandideh S., Ji J., Jo Y., Kamola P. J., Kanev G. K., Karacosta L., Karimi M., Kaski S., Kazanov M., Khamis A. M., Khan S. A., Kiani N. A., Kim A., Kim J., Kim K., Kim S., Kim Y., Kirk P. D. W., Kitano H., Klambauer G., Knowles D., Ko M., Kohn-Luque A., Kooistra A. J., Kuenemann M. A., Kuiper M., Kurz C., Kwon M., van Laarhoven T., Laegreid A., Lederer S., Lee H., Lee J., Lee Y. W., Lepp_aho E., Lewis R., Li J., Li L., Liley J., Lim W. K., Lin C., Liu Y., Lopez Y., Low J., Lysenko A., Machado D., Madhukar N., Maeyer D. D., Malpartida A. B., Mamitsuka H., Marabita F., Marchal K., Marttinen P., Mason D., Mazaheri A., Mehmood A., Mehreen A., Michaut M., Miller R. A., Mitsopoulos C., Modos D., Moerbeke M. V., 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., Niz C. D., Oliva B., Olsen C., Palmeri A., Panesar B., Papadopoulos S., Park J., 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 M. A., Ramnarine R., Reid J. E., Reyal F., Richardson S., Ricketts C., Rieswijk L., Rocha M., Rodriguez-Gonzalvez C., Roell K., Rotroff D., de Ruiter J. R., Rukawa P., Sadacca B., Safikhani Z., Safitri F., Sales-Pardo M., Sauer S., Schlichting M., Seoane J. A., Serra J., Shang M. -M., Sharma A., Sharma H., Shen Y., Shiga M., Shin M., Shkedy Z., Shopsowitz K., Sinai S., Skola D., Smirnov P., Soerensen I. F., Soerensen P., Song J. -H., Song S. O., Soufan O., Spitzmueller A., Steipe B., Suphavilai C., Tamayo S. P., Tamborero D., Tang J., Tanoli Z. -U. -R., Tarres-Deulofeu M., Tegner J., Thommesen L., Tonekaboni S. A. M., Tran H., Troyer E. D., Truong A., Tsunoda T., Turu G., Tzeng G. -Y., Verbeke L., Videla S., Vis D., Voronkov A., Votis K., Wang A., Wang H. -Q. H., Wang P. -W., Wang S., Wang W., Wang X., Wennerberg K., Wernisch L., Wessels L., van Westen G. J. P., Westerman B. A., White S. R., Willighagen E., Wurdinger T., Xie L., Xie S., Xu H., Yadav B., Yau C., Yeerna H., Yin J. W., Yu M., Yu M. H., Yun S. J., Zakharov A., Zamichos A., Zanin M., Zeng L., Zenil H., Zhang F., Zhang P., Zhang W., Zhao H., Zhao L., Zheng W., Zoufir A., Zucknick M., Jang I. S., Ghazoui Z., Ahsen M. E., Vogel R., Neto E. C., Norman T., Tang E. K. Y., Garnett M. J., Veroli G. Y. D., Fawell S., Stolovitzky G., Guinney J., Dry J. R., Saez-Rodriguez J., Menden, M, Wang, D, Mason, M, Szalai, B, Bulusu, K, Guan, Y, Yu, T, Kang, J, Jeon, M, Wolfinger, R, Nguyen, T, Zaslavskiy, M, Abante, J, Abecassis, B, Aben, N, Aghamirzaie, D, Aittokallio, T, Akhtari, F, Al-lazikani, B, Alam, T, Allam, A, Allen, C, de Almeida, M, Altarawy, D, Alves, V, Amadoz, A, Anchang, B, Antolin, A, Ash, J, Aznar, V, Ba-alawi, W, Bagheri, M, Bajic, V, Ball, G, Ballester, P, Baptista, D, Bare, C, Bateson, M, Bender, A, Bertrand, D, Wijayawardena, B, Boroevich, K, 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, G, Chen, H, Cheng, L, Chernomoretz, A, Chicco, D, Cho, K, Cho, S, Choi, D, Choi, J, Choi, K, Choi, M, Cock, M, Coker, E, Cortes-Ciriano, I, Cserzo, M, Cubuk, C, Curtis, C, Daele, D, Dang, C, Dijkstra, T, Dopazo, J, Draghici, S, Drosou, A, Dumontier, M, Ehrhart, F, Eid, F, Elhefnawi, M, Elmarakeby, H, van Engelen, B, Engin, H, de Esch, I, Evelo, C, Falcao, A, Farag, S, Fernandez-Lozano, C, Fisch, K, Flobak, A, Fornari, C, Foroushani, A, Fotso, D, Fourches, D, Friend, S, Frigessi, A, Gao, F, Gao, X, Gerold, J, 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, L, Heath, L, Hellton, K, Helmer-Citterich, M, Hidalgo, M, Hidru, D, Hill, S, Hochreiter, S, Hong, S, Hovig, E, Hsueh, Y, Hu, Z, Huang, J, Huang, R, Hunyady, L, Hwang, J, Hwang, T, Hwang, W, Hwang, Y, Isayev, O, Don't Walk, O, Jack, J, Jahandideh, S, Ji, J, Jo, Y, Kamola, P, Kanev, G, Karacosta, L, Karimi, M, Kaski, S, Kazanov, M, Khamis, A, Khan, S, Kiani, N, Kim, A, Kim, J, Kim, K, Kim, S, Kim, Y, Kirk, P, Kitano, H, Klambauer, G, Knowles, D, Ko, M, Kohn-Luque, A, Kooistra, A, Kuenemann, M, Kuiper, M, Kurz, C, Kwon, M, van Laarhoven, T, Laegreid, A, Lederer, S, Lee, H, Lee, J, Lee, Y, Lepp_aho, E, Lewis, R, Li, J, Li, L, Liley, J, Lim, W, Lin, C, Liu, Y, Lopez, Y, Low, J, Lysenko, A, Machado, D, Madhukar, N, Maeyer, D, Malpartida, A, Mamitsuka, H, Marabita, F, Marchal, K, Marttinen, P, Mason, D, Mazaheri, A, Mehmood, A, Mehreen, A, Michaut, M, Miller, R, Mitsopoulos, C, Modos, D, 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, Niz, C, Oliva, B, Olsen, C, Palmeri, A, Panesar, B, Papadopoulos, S, Park, J, 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, M, Ramnarine, R, Reid, J, Reyal, F, Richardson, S, Ricketts, C, Rieswijk, L, Rocha, M, Rodriguez-Gonzalvez, C, Roell, K, Rotroff, D, de Ruiter, J, Rukawa, P, Sadacca, B, Safikhani, Z, Safitri, F, Sales-Pardo, M, Sauer, S, Schlichting, M, Seoane, J, Serra, J, Shang, M, Sharma, A, Sharma, H, Shen, Y, Shiga, M, Shin, M, Shkedy, Z, Shopsowitz, K, Sinai, S, Skola, D, Smirnov, P, Soerensen, I, Soerensen, P, Song, J, Song, S, Soufan, O, Spitzmueller, A, Steipe, B, Suphavilai, C, Tamayo, S, Tamborero, D, Tang, J, Tanoli, Z, Tarres-Deulofeu, M, Tegner, J, Thommesen, L, Tonekaboni, S, Tran, H, Troyer, E, Truong, A, Tsunoda, T, Turu, G, Tzeng, G, Verbeke, L, Videla, S, Vis, D, Voronkov, A, Votis, K, Wang, A, Wang, H, Wang, P, Wang, S, Wang, W, Wang, X, Wennerberg, K, Wernisch, L, Wessels, L, van Westen, G, Westerman, B, White, S, Willighagen, E, Wurdinger, T, Xie, L, Xie, S, Xu, H, Yadav, B, Yau, C, Yeerna, H, Yin, J, Yu, M, Yun, S, Zakharov, A, Zamichos, A, Zanin, M, Zeng, L, Zenil, H, Zhang, F, Zhang, P, Zhang, W, Zhao, H, Zhao, L, Zheng, W, Zoufir, A, Zucknick, M, Jang, I, Ghazoui, Z, Ahsen, M, Vogel, R, Neto, E, Norman, T, Tang, E, Garnett, M, Veroli, G, Fawell, S, Stolovitzky, G, Guinney, J, Dry, J, Saez-Rodriguez, J, Menden M. P., Wang D., Mason M. J., Szalai B., Bulusu K. C., Guan Y., Yu T., Kang J., Jeon M., Wolfinger R., Nguyen T., Zaslavskiy M., Abante J., Abecassis B. S., Aben N., Aghamirzaie D., Aittokallio T., Akhtari F. S., Al-lazikani B., Alam T., Allam A., Allen C., de Almeida M. P., Altarawy D., Alves V., Amadoz A., Anchang B., Antolin A. A., Ash J. R., Aznar V. R., Ba-alawi W., Bagheri M., Bajic V., Ball G., Ballester P. J., Baptista D., Bare C., Bateson M., Bender A., Bertrand D., Wijayawardena B., Boroevich K. A., 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 G., Chen H., Cheng L., Chernomoretz A., Chicco D., Cho K. -H., Cho S., Choi D., Choi J., Choi K., Choi M., Cock M. D., Coker E., Cortes-Ciriano I., Cserzo M., Cubuk C., Curtis C., Daele D. V., Dang C. C., Dijkstra T., Dopazo J., Draghici S., Drosou A., Dumontier M., Ehrhart F., Eid F. -E., ElHefnawi M., Elmarakeby H., van Engelen B., Engin H. B., de Esch I., Evelo C., Falcao A. O., Farag S., Fernandez-Lozano C., Fisch K., Flobak A., Fornari C., Foroushani A. B. K., Fotso D. C., Fourches D., Friend S., Frigessi A., Gao F., Gao X., Gerold J. M., 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 L., Heath L. S., Hellton K. H., Helmer-Citterich M., Hidalgo M. R., Hidru D., Hill S. M., Hochreiter S., Hong S., Hovig E., Hsueh Y. -C., Hu Z., Huang J. K., Huang R. S., Hunyady L., Hwang J., Hwang T. H., Hwang W., Hwang Y., Isayev O., Don't Walk O. B., Jack J., Jahandideh S., Ji J., Jo Y., Kamola P. J., Kanev G. K., Karacosta L., Karimi M., Kaski S., Kazanov M., Khamis A. M., Khan S. A., Kiani N. A., Kim A., Kim J., Kim K., Kim S., Kim Y., Kirk P. D. W., Kitano H., Klambauer G., Knowles D., Ko M., Kohn-Luque A., Kooistra A. J., Kuenemann M. A., Kuiper M., Kurz C., Kwon M., van Laarhoven T., Laegreid A., Lederer S., Lee H., Lee J., Lee Y. W., Lepp_aho E., Lewis R., Li J., Li L., Liley J., Lim W. K., Lin C., Liu Y., Lopez Y., Low J., Lysenko A., Machado D., Madhukar N., Maeyer D. D., Malpartida A. B., Mamitsuka H., Marabita F., Marchal K., Marttinen P., Mason D., Mazaheri A., Mehmood A., Mehreen A., Michaut M., Miller R. A., Mitsopoulos C., Modos D., Moerbeke M. V., 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., Niz C. D., Oliva B., Olsen C., Palmeri A., Panesar B., Papadopoulos S., Park J., 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 M. A., Ramnarine R., Reid J. E., Reyal F., Richardson S., Ricketts C., Rieswijk L., Rocha M., Rodriguez-Gonzalvez C., Roell K., Rotroff D., de Ruiter J. R., Rukawa P., Sadacca B., Safikhani Z., Safitri F., Sales-Pardo M., Sauer S., Schlichting M., Seoane J. A., Serra J., Shang M. -M., Sharma A., Sharma H., Shen Y., Shiga M., Shin M., Shkedy Z., Shopsowitz K., Sinai S., Skola D., Smirnov P., Soerensen I. F., Soerensen P., Song J. -H., Song S. O., Soufan O., Spitzmueller A., Steipe B., Suphavilai C., Tamayo S. P., Tamborero D., Tang J., Tanoli Z. -U. -R., Tarres-Deulofeu M., Tegner J., Thommesen L., Tonekaboni S. A. M., Tran H., Troyer E. D., Truong A., Tsunoda T., Turu G., Tzeng G. -Y., Verbeke L., Videla S., Vis D., Voronkov A., Votis K., Wang A., Wang H. -Q. H., Wang P. -W., Wang S., Wang W., Wang X., Wennerberg K., Wernisch L., Wessels L., van Westen G. J. P., Westerman B. A., White S. R., Willighagen E., Wurdinger T., Xie L., Xie S., Xu H., Yadav B., Yau C., Yeerna H., Yin J. W., Yu M., Yu M. H., Yun S. J., Zakharov A., Zamichos A., Zanin M., Zeng L., Zenil H., Zhang F., Zhang P., Zhang W., Zhao H., Zhao L., Zheng W., Zoufir A., Zucknick M., Jang I. S., Ghazoui Z., Ahsen M. E., Vogel R., Neto E. C., Norman T., Tang E. K. Y., Garnett M. J., Veroli G. Y. D., Fawell S., Stolovitzky G., Guinney J., Dry J. R., and Saez-Rodriguez J.

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.

Published
2019

4. Crowdsourced mapping of unexplored target space of kinase inhibitors

Author

Cichonska, A, Ravikumar, B, Allaway, RJ, Wan, F, Park, S, Isayev, O, Li, S, Mason, M, Lamb, A, Tanoli, Z, Jeon, M, Kim, S, Popova, M, Capuzzi, S, Zeng, J, Dang, K, Koytiger, G, Kang, J, Wells, CI, Willson, TM, Oprea, TI, Schlessinger, A, Drewry, DH, Stolovitzky, G, Wennerberg, K, Guinney, J, Aittokallio, T, Tan, M, Huang, C-H, Shih, ESC, Chen, T-M, Wu, C-H, Fang, W-Q, Chen, J-Y, Hwang, M-J, Wang, X, Ben Guebila, M, Shamsaei, B, Singh, S, Nguyen, Thin, Karimi, M, Wu, D, Wang, Z, Shen, Y, Ozturk, H, Ozkirimli, E, Ozgur, A, Lim, H, Xie, L, Kanev, GK, Kooistra, AJ, Westerman, BA, Terzopoulos, P, Ntagiantas, K, Fotis, C, Alexopoulos, L, Boeckaerts, D, Stock, M, De Baets, B, Briers, Y, Luo, Y, Hu, H, Peng, J, Dogan, T, Rifaioglu, AS, Atas, H, Atalay, RC, Atalay, V, Martin, MJ, Lee, J, Yun, S, Kim, B, Chang, B, Turu, G, Misak, A, Szalai, B, Hunyady, L, Lienhard, M, Prasse, P, Bachmann, I, Ganzlin, J, Barel, G, Herwig, R, Orsolic, D, Lucic, B, Stepanic, V, Smuc, T, Cichonska, A, Ravikumar, B, Allaway, RJ, Wan, F, Park, S, Isayev, O, Li, S, Mason, M, Lamb, A, Tanoli, Z, Jeon, M, Kim, S, Popova, M, Capuzzi, S, Zeng, J, Dang, K, Koytiger, G, Kang, J, Wells, CI, Willson, TM, Oprea, TI, Schlessinger, A, Drewry, DH, Stolovitzky, G, Wennerberg, K, Guinney, J, Aittokallio, T, Tan, M, Huang, C-H, Shih, ESC, Chen, T-M, Wu, C-H, Fang, W-Q, Chen, J-Y, Hwang, M-J, Wang, X, Ben Guebila, M, Shamsaei, B, Singh, S, Nguyen, Thin, Karimi, M, Wu, D, Wang, Z, Shen, Y, Ozturk, H, Ozkirimli, E, Ozgur, A, Lim, H, Xie, L, Kanev, GK, Kooistra, AJ, Westerman, BA, Terzopoulos, P, Ntagiantas, K, Fotis, C, Alexopoulos, L, Boeckaerts, D, Stock, M, De Baets, B, Briers, Y, Luo, Y, Hu, H, Peng, J, Dogan, T, Rifaioglu, AS, Atas, H, Atalay, RC, Atalay, V, Martin, MJ, Lee, J, Yun, S, Kim, B, Chang, B, Turu, G, Misak, A, Szalai, B, Hunyady, L, Lienhard, M, Prasse, P, Bachmann, I, Ganzlin, J, Barel, G, Herwig, R, Orsolic, D, Lucic, B, Stepanic, V, and Smuc, T

Abstract

AbstractDespite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound–kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome.

Published
2021

5. THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors

Author

Alexander, SPH, Christopoulos, A, Davenport, AP, Kelly, E, Mathie, A, Peters, JA, Veale, EL, Armstrong, JF, Faccenda, E, Harding, SD, Pawson, AJ, Southan, C, Davies, JA, Abbracchio, MP, Alexander, W, Al-hosaini, K, Baeck, M, Barnes, NM, Bathgate, R, Beaulieu, J-M, Bernstein, KE, Bettler, B, Birdsall, NJM, Blaho, V, Boulay, F, Bousquet, C, Braeuner-Osborne, H, Burnstock, G, Calo, G, Castano, JP, Catt, K, Ceruti, S, Chazot, P, Chiang, N, Chini, B, Chun, J, Cianciulli, A, Civelli, O, Clapp, LH, Couture, R, Csaba, Z, Dahlgren, C, Dent, G, Singh, KD, Douglas, SD, Dournaud, P, Eguchi, S, Escher, E, Filardo, EJ, Fong, T, Fumagalli, M, Gainetdinov, RR, de Gasparo, M, Gerard, C, Gershengorn, M, Gobeil, F, Goodfriend, TL, Goudet, C, Gregory, KJ, Gundlach, AL, Hamann, J, Hanson, J, Hauger, RL, Hay, DL, Heinemann, A, Hollenberg, MD, Holliday, ND, Horiuchi, M, Hoyer, D, Hunyady, L, Husain, A, IJzerman, AP, Inagami, T, Jacobson, KA, Jensen, RT, Jockers, R, Jonnalagadda, D, Karnik, S, Kaupmann, K, Kemp, J, Kennedy, C, Kihara, Y, Kitazawa, T, Kozielewicz, P, Kreienkamp, H-J, Kukkonen, JP, Langenhan, T, Leach, K, Lecca, D, Lee, JD, Leeman, SE, Leprince, J, Li, XX, Williams, TL, Lolait, SJ, Lupp, A, Macrae, R, Maguire, J, Mazella, J, McArdle, CA, Melmed, S, Michel, MC, Miller, LJ, Mitolo, V, Mouillac, B, Mueller, CE, Murphy, P, Nahon, J-L, Ngo, T, Norel, X, Nyimanu, D, Ocarroll, A-M, Offermanns, S, Panaro, MA, Parmentier, M, Pertwee, RG, Pin, J-P, Prossnitz, ER, Quinn, M, Ramachandran, R, Ray, M, Reinscheid, RK, Rondard, P, Rovati, GE, Ruzza, C, Sanger, GJ, Schoeneberg, T, Schulte, G, Schulz, S, Segaloff, DL, Serhan, CN, Stoddart, LA, Sugimoto, Y, Summers, R, Tan, VP, Thal, D, Thomas, WW, Timmermans, PMWM, Tirupula, K, Tulipano, G, Unal, H, Unger, T, Valant, C, Vanderheyden, P, Vaudry, D, Vaudry, H, Vilardaga, J-P, Walker, CS, Wang, JM, Ward, DT, Wester, H-J, Willars, GB, Woodruff, TM, Yao, C, Ye, RD, Alexander, SPH, Christopoulos, A, Davenport, AP, Kelly, E, Mathie, A, Peters, JA, Veale, EL, Armstrong, JF, Faccenda, E, Harding, SD, Pawson, AJ, Southan, C, Davies, JA, Abbracchio, MP, Alexander, W, Al-hosaini, K, Baeck, M, Barnes, NM, Bathgate, R, Beaulieu, J-M, Bernstein, KE, Bettler, B, Birdsall, NJM, Blaho, V, Boulay, F, Bousquet, C, Braeuner-Osborne, H, Burnstock, G, Calo, G, Castano, JP, Catt, K, Ceruti, S, Chazot, P, Chiang, N, Chini, B, Chun, J, Cianciulli, A, Civelli, O, Clapp, LH, Couture, R, Csaba, Z, Dahlgren, C, Dent, G, Singh, KD, Douglas, SD, Dournaud, P, Eguchi, S, Escher, E, Filardo, EJ, Fong, T, Fumagalli, M, Gainetdinov, RR, de Gasparo, M, Gerard, C, Gershengorn, M, Gobeil, F, Goodfriend, TL, Goudet, C, Gregory, KJ, Gundlach, AL, Hamann, J, Hanson, J, Hauger, RL, Hay, DL, Heinemann, A, Hollenberg, MD, Holliday, ND, Horiuchi, M, Hoyer, D, Hunyady, L, Husain, A, IJzerman, AP, Inagami, T, Jacobson, KA, Jensen, RT, Jockers, R, Jonnalagadda, D, Karnik, S, Kaupmann, K, Kemp, J, Kennedy, C, Kihara, Y, Kitazawa, T, Kozielewicz, P, Kreienkamp, H-J, Kukkonen, JP, Langenhan, T, Leach, K, Lecca, D, Lee, JD, Leeman, SE, Leprince, J, Li, XX, Williams, TL, Lolait, SJ, Lupp, A, Macrae, R, Maguire, J, Mazella, J, McArdle, CA, Melmed, S, Michel, MC, Miller, LJ, Mitolo, V, Mouillac, B, Mueller, CE, Murphy, P, Nahon, J-L, Ngo, T, Norel, X, Nyimanu, D, Ocarroll, A-M, Offermanns, S, Panaro, MA, Parmentier, M, Pertwee, RG, Pin, J-P, Prossnitz, ER, Quinn, M, Ramachandran, R, Ray, M, Reinscheid, RK, Rondard, P, Rovati, GE, Ruzza, C, Sanger, GJ, Schoeneberg, T, Schulte, G, Schulz, S, Segaloff, DL, Serhan, CN, Stoddart, LA, Sugimoto, Y, Summers, R, Tan, VP, Thal, D, Thomas, WW, Timmermans, PMWM, Tirupula, K, Tulipano, G, Unal, H, Unger, T, Valant, C, Vanderheyden, P, Vaudry, D, Vaudry, H, Vilardaga, J-P, Walker, CS, Wang, JM, Ward, DT, Wester, H-J, Willars, GB, Woodruff, TM, Yao, C, and Ye, RD

Abstract

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Published
2021

23. THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors

Author

Alexander, SPH, Christopoulos, A, Davenport, AP, Kelly, E, Mathie, A, Peters, JA, Veale, EL, Armstrong, JF, Faccenda, E, Harding, SD, Pawson, AJ, Sharman, JL, Southan, C, Davies, JA, Arumugam, TV, Bennett, A, Sjogren, B, Sobey, C, Wong, SS, Abbracchio, MP, Alexander, W, Al-hosaini, K, Back, M, Beaulieu, J-M, Bernstein, KE, Bettler, B, Birdsall, NJM, Blaho, V, Bousquet, C, Brauner-Osborne, H, Burnstock, G, Calo, G, Castano, JP, Catt, KJ, Ceruti, S, Chazot, P, Chiang, N, Chun, J, Cianciulli, A, Clapp, LH, Couture, R, Csaba, Z, Dent, G, Singh, KD, Douglas, SD, Dournaud, P, Eguchi, S, Escher, E, Filardo, E, Fong, TM, Fumagalli, M, Gainetdinov, RR, de Gasparo, M, Gershengorn, M, Gobeil, F, Goodfriend, TL, Goudet, C, Gregory, KJ, Gundlach, AL, Hamann, J, Hanson, J, Hauger, RL, Hay, D, Heinemann, A, Hollenberg, MD, Holliday, ND, Horiuchi, M, Hoyer, D, Hunyady, L, Husain, A, Ijzerman, AP, Inagami, T, Jacobson, KA, Jensen, RT, Jockers, R, Jonnalagadda, D, Karnik, S, Kaupmann, K, Kemp, J, Kennedy, C, Kihara, Y, Kozielewicz, P, Kreienkamp, H-J, Kukkonen, JP, Langenhan, T, Leach, K, Lecca, D, Lee, JD, Leeman, SE, Leprince, J, Lolait, SJ, Lupp, A, Macrae, R, Maguire, J, Mazella, J, McArdle, CA, Melmed, S, Michel, MC, Miller, L, Mitolo, V, Mouillac, B, Murphy, PM, Nahon, J-L, Norel, X, Nyimanu, D, O'Carroll, A-M, Offermanns, S, Panaro, MA, Pertwee, RG, Pin, J-P, Prossnitz, E, Ramachandran, R, Reinscheid, RK, Rondard, P, Rovati, GE, Ruzza, C, Sanger, G, Schoeneberg, T, Schulte, G, Schulz, S, Segaloff, DL, Serhan, CN, Stoddart, LA, Sugimoto, Y, Summers, R, Tan, V, Thomas, W, Timmermans, PBMWM, Tirupula, K, Tulipano, G, Unal, H, Unger, T, Vanderheyden, P, Vaudry, D, Vaudry, H, Vilardaga, J-P, Walker, CS, Ward, DT, Wester, H-J, Willars, GB, Williams, TL, Woodruff, TM, Yao, C, Aldrich, RW, Becirovic, E, Biel, M, Catterall, WA, Conner, AC, Davies, P, Delling, M, Di Virgilio, F, Falzoni, S, George, C, Goldstein, SAN, Grissmer, S, Ha, K, Hammelmann, V, Hanukoglu, I, Jarvis, M, Jensen, AA, Kaczmarek, LK, Kellenberger, S, King, B, Lynch, JW, Perez-Reyes, E, Plant, LD, Rash, LD, Ren, D, Sivilotti, LG, Smart, TG, Snutch, TP, Tian, J, Van den Eynde, C, Vriens, J, Wei, AD, Winn, BT, Wulff, H, Xu, H, Yue, L, Zhang, X, Zhu, M, Coons, L, Fuller, P, Korach, KS, Young, M, Bryant, C, Farndale, RW, Hobbs, A, Jarvis, GE, MacEwan, D, Monie, TP, Waldman, S, Beuve, A, Boison, D, Brouckaert, P, Burnett, JC, Burns, K, Dessauer, C, Friebe, A, Garthwaite, J, Gertsch, J, Helsby, N, Izzo, AA, Koesling, D, Kuhn, M, Ostrom, R, Papapetropoulos, A, Potter, LR, Pyne, NJ, Pyne, S, Russwurm, M, Schmidt, HHHW, Seifert, R, Stasch, J-P, Szabo, C, van der Stelt, M, van der Vliet, A, Watts, V, Anderson, CMH, Broer, S, Dawson, P, Hagenbuch, B, Hammond, JR, Hancox, J, Inui, K-I, Kanai, Y, Kemp, S, Thwaites, DT, Verri, T, Alexander, SPH, Christopoulos, A, Davenport, AP, Kelly, E, Mathie, A, Peters, JA, Veale, EL, Armstrong, JF, Faccenda, E, Harding, SD, Pawson, AJ, Sharman, JL, Southan, C, Davies, JA, Arumugam, TV, Bennett, A, Sjogren, B, Sobey, C, Wong, SS, Abbracchio, MP, Alexander, W, Al-hosaini, K, Back, M, Beaulieu, J-M, Bernstein, KE, Bettler, B, Birdsall, NJM, Blaho, V, Bousquet, C, Brauner-Osborne, H, Burnstock, G, Calo, G, Castano, JP, Catt, KJ, Ceruti, S, Chazot, P, Chiang, N, Chun, J, Cianciulli, A, Clapp, LH, Couture, R, Csaba, Z, Dent, G, Singh, KD, Douglas, SD, Dournaud, P, Eguchi, S, Escher, E, Filardo, E, Fong, TM, Fumagalli, M, Gainetdinov, RR, de Gasparo, M, Gershengorn, M, Gobeil, F, Goodfriend, TL, Goudet, C, Gregory, KJ, Gundlach, AL, Hamann, J, Hanson, J, Hauger, RL, Hay, D, Heinemann, A, Hollenberg, MD, Holliday, ND, Horiuchi, M, Hoyer, D, Hunyady, L, Husain, A, Ijzerman, AP, Inagami, T, Jacobson, KA, Jensen, RT, Jockers, R, Jonnalagadda, D, Karnik, S, Kaupmann, K, Kemp, J, Kennedy, C, Kihara, Y, Kozielewicz, P, Kreienkamp, H-J, Kukkonen, JP, Langenhan, T, Leach, K, Lecca, D, Lee, JD, Leeman, SE, Leprince, J, Lolait, SJ, Lupp, A, Macrae, R, Maguire, J, Mazella, J, McArdle, CA, Melmed, S, Michel, MC, Miller, L, Mitolo, V, Mouillac, B, Murphy, PM, Nahon, J-L, Norel, X, Nyimanu, D, O'Carroll, A-M, Offermanns, S, Panaro, MA, Pertwee, RG, Pin, J-P, Prossnitz, E, Ramachandran, R, Reinscheid, RK, Rondard, P, Rovati, GE, Ruzza, C, Sanger, G, Schoeneberg, T, Schulte, G, Schulz, S, Segaloff, DL, Serhan, CN, Stoddart, LA, Sugimoto, Y, Summers, R, Tan, V, Thomas, W, Timmermans, PBMWM, Tirupula, K, Tulipano, G, Unal, H, Unger, T, Vanderheyden, P, Vaudry, D, Vaudry, H, Vilardaga, J-P, Walker, CS, Ward, DT, Wester, H-J, Willars, GB, Williams, TL, Woodruff, TM, Yao, C, Aldrich, RW, Becirovic, E, Biel, M, Catterall, WA, Conner, AC, Davies, P, Delling, M, Di Virgilio, F, Falzoni, S, George, C, Goldstein, SAN, Grissmer, S, Ha, K, Hammelmann, V, Hanukoglu, I, Jarvis, M, Jensen, AA, Kaczmarek, LK, Kellenberger, S, King, B, Lynch, JW, Perez-Reyes, E, Plant, LD, Rash, LD, Ren, D, Sivilotti, LG, Smart, TG, Snutch, TP, Tian, J, Van den Eynde, C, Vriens, J, Wei, AD, Winn, BT, Wulff, H, Xu, H, Yue, L, Zhang, X, Zhu, M, Coons, L, Fuller, P, Korach, KS, Young, M, Bryant, C, Farndale, RW, Hobbs, A, Jarvis, GE, MacEwan, D, Monie, TP, Waldman, S, Beuve, A, Boison, D, Brouckaert, P, Burnett, JC, Burns, K, Dessauer, C, Friebe, A, Garthwaite, J, Gertsch, J, Helsby, N, Izzo, AA, Koesling, D, Kuhn, M, Ostrom, R, Papapetropoulos, A, Potter, LR, Pyne, NJ, Pyne, S, Russwurm, M, Schmidt, HHHW, Seifert, R, Stasch, J-P, Szabo, C, van der Stelt, M, van der Vliet, A, Watts, V, Anderson, CMH, Broer, S, Dawson, P, Hagenbuch, B, Hammond, JR, Hancox, J, Inui, K-I, Kanai, Y, Kemp, S, Thwaites, DT, and Verri, T

Abstract

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Published
2019

24. Capacitative Ca2+ influx in adrenal glomerulosa cells: possible role in angiotensin II response

Author

Rohacs, T., Bago, A., Deak, F., Hunyady, L., and Spat, A.

Subjects
Calcium in the body -- Research, Kidney glomerulus -- Physiological aspects, Adenosine triphosphatase -- Physiological aspects, Biological sciences
Abstract

A study of the effect of intracellular Ca2+ store removal on Ca2+ influx in rat glomerulosa cells by inhibiting sarco/endoplasmic reticulum-type Ca2+-ATPase with thapsigargin or 2, 5-di-(t-butyl)-1,4-benzohydroquinone reveals a sustained increase in cytoplasmic Ca2+ concentration due to the two inhibitors. A similar initial increase in a Ca2+-free medium, which is not maintained, demonstrates the need for Ca2+ influx for the maintenance. The increase in intracellular Ca2+ concentration in a Ca2+-free medium after the readdition of Ca2+ in thapsigargin-treated cells confirms the role of Ca2+ influx.

Published
1994

46. Desensitization of the Y1 cell adrenocorticotropin receptor: evidence for a restricted heterologous mechanism implying a role for receptor-effector complexes.

Author

Baig, A H, Swords, F M, Noon, L A, King, P J, Hunyady, L, and Clark, A J

Abstract

Receptor desensitization provides a potential mechanism for the regulation of adrenocortical adrenocorticotropin (ACTH) responsiveness. Using the mouse adrenocortical Y1 cell line we demonstrate that ACTH effectively desensitizes the cAMP response of its own receptor, the melanocortin 2 receptor (MC2R), in these cells with a maximal effect between 30 and 60 min. Neither forskolin nor isoproterenol (in Y1 cells stably transfected with the beta(2)-adrenergic receptor) desensitize this ACTH response. ACTH desensitizes its receptor at concentrations at which only a fraction of receptors are occupied, implying that this mechanism acts on agonist-unoccupied receptors. Y1 cells express G protein-coupled receptor kinase (GRK) 2 and 5, but stable expression of a dominant negative GRK2 (K220W) only marginally reduces the desensitization by ACTH. The protein kinase A (PKA) inhibitor, H89, extinguishes almost the entire desensitization response over the initial 30-min period at all concentrations of ACTH. A mutant MC2R in which the single consensus PKA phosphorylation site has been mutated (S208A) when expressed in MC2R-negative Y6 cells is also unable to desensitize. These data imply a heterologous, PKA-dependent, mode of desensitization, which is restricted to agonist-occupied and -unoccupied MC2R, possibly as a consequence of receptor/effector complexes that functionally compartmentalize this receptor.

Published
2001
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48. Na+-H+ and Na+-Ca2+ exchange in glomerulosa cells: possible role in control of aldosterone production

Author

Hunyady, L., Kayser, S., Cragoe, E. J., Balla, I., Balla, T., and Spat, A.

Abstract

Sodium uptake by rat adrenal glomerulosa cells was stimulated by intracellular acidosis evoked by Na+-propionate. This process was inhibited by 5-(N,N-hexamethylene) amiloride (HMA), a known inhibitor of the Na+-H+ exchange. These experiments demonstrate the existence of the Na+-H+ exchange in glomerulosa cells. Although amiloride inhibited the angiotensin II- and adrenocorticotropic hormone (ACTH)-induced aldosterone response, HMA, a more specific inhibitor of Na+-H+ exchange, failed to do that. 45Ca2+ influx and efflux were dependent on intra- and extracellular Na+ concentrations. Amiloride analogues, known to inhibit Na+-Ca2+ exchange, reduced basal 45Ca influx. Although we could not reveal the activation of Na+-Ca2+ exchange by angiotensin II, inhibitors of Na+-Ca2+ exchange also inhibited the angiotensin- and ACTH-induced aldosterone response of glomerulosa cells. Our results suggest that Na+-Ca2+ exchange supports the maintenance of basal Ca2+ level in the cytoplasma of glomerulosa cells, and amiloride derivatives inhibit aldosterone production by reducing Ca2+ level below resting values.

Published
1988
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49. Effects of lithium on angiotensin‐stimulated phosphatidylinositol turnover and aldosterone production in adrenal glomerulosa cells: a possible causal relationship

Author

Balla, T., Enyedi, P., Hunyady, L., and Spät, A.

Abstract

Turnover of 32P‐labelled phosphatidylinositol (PI) was examined in isolated adrenal glomerulosa cells. Increased incorporation of [32P] phosphate into PI in response to angiotensin II was completely prevented by Li+. A simultaneous accumulation of 32P activity in phosphatidic acid (PA) was also observed. Angiotensin II increased the breakdown of PI despite the presence of Li+. These results suggest that Li is a suitable tool to interrupt the accelerated PI cycle in angiotensin‐stimulated cells. Aldosterone production of superfused cells was inhibited by Li+when the cells were stimulated with angiotensin II. On the other hand, Li+did not inhibit the aldosterone response of the cells to ACTH, a hormone which acts via cyclic AMP and does not enhance PI turnover in these cells. On the basis of these results, we assume that the inhibitory effect of Li+on aldosterone production is related to its effect on PI turnover.

Published
1984
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50. Angiotensin II and guanine nucleotides stimulate formation of inositol 1,4,5-trisphosphate and its metabolites in permeabilized adrenal glomerulosa cells.

Author

Baukal, A J, Balla, T, Hunyady, L, Hausdorff, W, Guillemette, G, and Catt, K J

Abstract

Angiotensin II (AII) interacts with specific receptors in the adrenal glomerulosa cell and stimulates the hydrolysis of plasma membrane phosphoinositides by phospholipase C, with production of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) and subsequent mobilization of intracellular Ca2+. In electrically permeabilized, [3H]inositol-labeled glomerulosa cells, AII stimulated Ins-1,4,5-P3 production within 15 s with half-maximal potency of 10(-9) M. The nonhydrolyzable GTP analog, guanosine 5'-O-thiotriphosphate (GTP gamma S), stimulated Ins-1,4,5-P3 formation in a dose-dependent manner with half-maximal effect at 10(-7) M. AII-activated Ins-1,4,5-P3 production was further increased by guanine nucleotides. The rate at which GTP gamma S-stimulated inositol polyphosphate production was consistently slower than that of AII. In adrenal membrane preparations, GTP gamma S-stimulated polyphosphoinositide hydrolysis was enhanced by Ca2+, with half-maximal activity at 300 nM free Ca2+. Ins-1,4,5-P3 formation was also increased by NaF, further indicating the involvement of a guanine nucleotide regulatory protein. In addition to Ins-1,4,5-P3 and its metabolites formed during degradation via the 4-monophosphate pathway, AII and GTP gamma S stimulated the formation of the phosphorylated metabolite inositol 1,3,4,5-tetrakisphosphate and inositol 1,3,4-trisphosphate in permeabilized cells. The absence of a significant rise in inositol 1-monophosphate indicated that phosphatidylinositol hydrolysis was not stimulated by AII or GTP gamma S. Pretreatment of glomerulosa cells with pertussis toxin for 12 h before permeabilization did not inhibit AII- or GTP gamma S-stimulated inositol polyphosphate formation. However, treatment with cholera toxin, forskolin, or 8-Br-cAMP for 12 h enhanced both basal and ligand-stimulated Ins-1,4,5-P3 production. These observations suggest that agonist binding to the AII receptor activates a polyphosphoinositide-specific phospholipase C in the adrenal glomerulosa cell, and that a distinctive guanine regulatory protein is involved in this mechanism.

Published
1988
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