Efforts of functional characterization of cancer-associated somatic mutations in oncogenes have been largely incomprehensive because they do not encompass the large majority. I have developed a pipeline to analyze thousands of variants of an oncogenic kinase gene in a single assay, I call iSCREAM (in vitro SCReen for Activating Mutation). We are developing the iSCREAM workflow to preemptively identify and characterize on-target secondary mutations that can cause therapeutic resistance, and then subsequently identify therapies that would potentially work for those resistant mutations.