Community Assessment to Advance Computational Prediction of Cancer Drug Combinations in a Pharmacogenomic Screen

Nat Commun. 2019 Jun 17;10(1):2674. doi: 10.1038/s41467-019-09799-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / antagonists & inhibitors
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benchmarking
  • Biomarkers, Tumor / genetics
  • Cell Line, Tumor
  • Computational Biology / methods*
  • Computational Biology / standards
  • Datasets as Topic
  • Drug Antagonism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Genomics / methods
  • Humans
  • Molecular Targeted Therapy / methods
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Pharmacogenetics / methods*
  • Pharmacogenetics / standards
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphoinositide-3 Kinase Inhibitors
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • Phosphoinositide-3 Kinase Inhibitors
  • ADAM17 Protein
  • ADAM17 protein, human