Harnessing machine learning to find synergistic combinations for FDA-approved cancer drugs

Combination therapy is a fundamental strategy in cancer chemotherapy. It involves administering two or more anti-cancer agents to increase efficacy and overcome multidrug resistance compared to monotherapy. However, drug combinations can exhibit synergy, additivity, or antagonism. This study presents a machine learning framework to classify and predict cancer drug combinations. The framework utilizes several key steps including data collection and annotation from the O'Neil drug interaction dataset, data preprocessing, stratified splitting into training and test sets, construction and evaluation of classification models to categorize combinations as synergistic, additive, or antagonistic, application of regression models to predict combination sensitivity scores for enhanced predictions compared to prior work, and the last step is examination of drug features and mechanisms of action to understand synergy behaviors for optimal combinations. The models identified combination pairs most likely to synergize against different cancers. Kinase inhibitors combined with mTOR inhibitors, DNA damage-inducing drugs or HDAC inhibitors showed benefit, particularly for ovarian, melanoma, prostate, lung and colorectal carcinomas. Analysis highlighted Gemcitabine, MK-8776 and AZD1775 as frequently synergizing across cancer types. This machine learning framework provides a valuable approach to uncover more effective multi-drug regimens.