An integrated computational strategy to predict personalized cancer drug combinations by reversing drug resistance signatures

Drug resistance currently poses the greatest barrier to cancer treatments. To overcome drug resistance, drug combination therapy has been proposed as a promising treatment strategy. Herein, we present Re-Sensitizing Drug Prediction (RSDP), a novel computational strategy, for predicting the personalized cancer drug combination A + B by reversing the resistance signature of drug A. The process integrates multiple biological features using a robust rank aggregation algorithm, including Connectivity Map, synthetic lethality, synthetic rescue, pathway, and drug target. Bioinformatics assessments revealed that RSDP achieved a relatively accurate prediction performance for identifying personalized combinational re-sensitizing drug B against cell line–specific intrinsic resistance, cell line–specific acquired resistance, and patient-specific intrinsic resistance to drug A. In addition, we developed the largest resource of cell line–specific cancer drug resistance signatures, including intrinsic and acquired resistance, as a byproduct of the proposed strategy. The findings indicate that personalized drug resistance signature reversal is a promising strategy for identifying personalized drug combinations, which may guide future clinical decisions regarding personalized medicine. •A novel computational strategy Re-Sensitizing Drug Prediction (RSDP) was proposed.•RSDP predicts personalized drug A + Bs by drug A resistance signature reversal.•RSDP can effectively predict cell line-specific drug combinations A + B.•RSDP can achieve a relatively reliable prediction for patient-specific drug A + Bs.•The largest cell line-specific Cancer Drug Resistance Signature Resource was built.