Abstract
A novel data mining procedure is proposed for identifying potential pathway-gene biomarkers from preclinical drug sensitivity data for predicting clinical responses to erlotinib or sorafenib. The analysis applies linear ridge regression modeling to generate a small (N~1000) set of baseline gene expressions that jointly yield quality predictions of preclinical drug sensitivity data and clinical responses. Standard clustering of the pathway-gene combinations from gene set enrichment analysis of this initial gene set, according to their shared appearance in molecular function pathways, yields a reduced (N~300) set of potential pathway-gene biomarkers. A modified method for quantifying pathway fitness is used to determine smaller numbers of over and under expressed genes that correspond with favorable and unfavorable clinical responses. Detailed literature-based evidence is provided in support of the roles of these under and over expressed genes in compound efficacy. RandomForest analysis of potential pathway-gene biomarkers finds average treatment prediction errors of 10% and 22%, respectively, for patients receiving erlotinib or sorafenib that had a favorable clinical response. Higher errors were found for both compounds when predicting an unfavorable clinical response. Collectively these results suggest complementary roles for biomarker genes and biomarker pathways when predicting clinical responses from preclinical data.