Regulators of Ras oncogenic signaling, particularly non-essential genes, are critically important targets for drug discovery. Long et al. show that ZRANB3, a non-essential gene, is required for H-Ras-induced focus formation. This process is inhibited by an RNR-?-targeting drug, clofarabine that promotes RNR-? nuclear translocation, thereby ushering previously unrecognized therapeutic opportunities.