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

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

Book Reviews

- P.J. Worsley, Ktut Ginarsa, Prasasti Baru Ragajaya 6 April 1155. Direktorat Bahasa dan Kesusastraan, Direktorat Djendral Kebudajaan, Departemen Pendidikan dan Kebudajaan, Tjabang Singaradja, 1968. XVI, 54 p., 3 maps. - Th. J. Gerold-Scheepers, M.A. Jaspan, Traditional medical theory in Southeast Asia. An inaugural lecture, University of Hull, Hull 1969. 36 pag. - Renato Rosaldo, Don V. Hart, Bisayan Filipino and Malayan Humoral Pathologies: Folk medicine and ethnohistory in Southeast Asia. Ithaca, New York; Department of Asian Studies, Cornell University. Data Paper: No. 76. 96 p. - Pierre J. Simon, W.E. Willmott, The political structure of the Chinese community in Cambodia. L.S.E. Monographs nr. 42. The Athlone Press, London 1970. 211 p. - Vivien van Geen, Owen M. Lynch, The politics of untouchability (Social mobility and social change in a city of India). Columbia University Press, New York and London, 1969. XIV-251 pp. - W.F.L. Buschkens, Silvia W. de Groot, Djuka society and social change: History of an attempt to develop a bush negro community in Surinam 1917-1926. Van Gorcum &amp; Comp. N.V. - Doctor H.J. Prakke &amp; H.M.G. Prakke, Assen 1969. XVI + 256 p., met twee kaarten, 12 fotografieën en een bibliografie van Willem Frederik van Lier. - W.F.L. Buschkens, A. Polak-Eltz, Afro-Amerikaanse godsdiensten en culten. J.J. Romen &amp; Zonen, Roermond 1970. 221 blz., 30 ills.</jats:p

Type I Interferon and NF-κB Activation Elicited by Herpes Simplex Virus gH/gL via αvβ3 Integrin in Epithelial and Neuronal Cell Lines

αvβ3 integrin represents a novel sensing system which detects herpes simplex virus (HSV) and bacterial constituents. In cooperation with Toll-like receptor 2 (TLR2), it elicits an innate response that leads to activation of type I interferon (IFN), NF-κB, and a specific set of cytokines. We report that this defensive branch is functional in cells which represent experimental models of epithelial, including keratinocytic, and neuronal cells. These are the major targets of HSV in vivo. HSV entered the three cell lines via distinct routes. Hence, the defensive response was independent of the route of virus entry. Soluble gH/gL sufficed to elicit type I IFN and NF-κB activation and represents the viral pathogen-associated molecular pattern (PAMP) of this defense system