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- Menden, MP, et al.
(author)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Journal article (peer-reviewed)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.
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2. |
- Adler, M., et al.
(author)
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Tacnode GUE-minor processes and double Aztec diamonds
- 2015
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In: Probability theory and related fields. - : Springer Science and Business Media LLC. - 0178-8051 .- 1432-2064. ; 162:1-2, s. 275-325
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Journal article (peer-reviewed)abstract
- We study determinantal point processes arising in random domino tilings of a double Aztec diamond, a region consisting of two overlapping Aztec diamonds. At a turning point in a single Aztec diamond where the disordered region touches the boundary, the natural limiting process is the GUE-minor process. Increasing the size of a double Aztec diamond while keeping the overlap between the two Aztec diamonds finite, we obtain a new determinantal point process which we call the tacnode GUE-minor process. This process can be thought of as two colliding GUE-minor processes. As part of the derivation of the particle kernel whose scaling limit naturally gives the tacnode GUE-minor process, we find the inverse Kasteleyn matrix for the dimer model version of the Double Aztec diamond.
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