Network-based targeting strategies represent a promising therapeutic approach for the treatment of diseases that lack strong and actionable drivers. Using an integrated phenotypic screening and phosphoproteomics strategy, Kuenzi et al. report that the FDA-approved ALK inhibitor ceritinib exhibits activity in several ALK-negative non-small-cell lung cancer cell lines through simultaneous inhibition of multiple non-canonical targets (namely FAK1, IGF1R, RSK1 and RSK2), which is largely dependent on the downstream signalling effector YB1. Ceritinib synergized with paclitaxel, particularly in cells expressing high FAK1 autophosphorylation.