Precision oncology workflows rely heavily on genomic identification of oncogenic driver mutations or the functional loss of tumor suppressors. These pipelines can identify single-agent treatments for patients, but monotherapy is often insufficient and can drive resistance. Recently, functional drug screening has been employed to evaluate tumor-specific drug sensitivities that complement molecular testing. We describe a resistance evaluation after first line exposure (REFLEX) multi-omic paradigm using drug-induced molecular changes to prioritize effective hits from combination screening. In KRAS-mutant cancer models, trametinib treatment caused dysregulation of the purine biosynthetic pathway driven by reductions in enzyme GART. This induced vulnerability nominated purine analog 6-thioguanine as a synergistic partner. Across diverse KRAS-mutant lineages, trametinib-induced GART loss predicts sensitivity to the combination. In vivo, the treatment significantly increases overall survival without systemic toxicity. Integrating drug-induced multi-omic changes with functional screening identifies therapeutic strategies, supporting the use of purine analogs with MEK inhibitors for KRAS-mutant tumors.