The study investigates the potential for growth-factor-driven resistance to anticancer kinase inhibitors. Using a panel of kinase-dependent human cancer cell lines, the researchers found that exposure to receptor tyrosine kinase (RTK) ligands can rescue cells from drug-induced growth inhibition. The most effective ligands were hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and neuregulin 1 (NRG1). These ligands reactivated survival signaling pathways, particularly the PI(3)K-AKT and MAPK pathways, despite the presence of the targeted kinase inhibitor. The findings highlight the extensive redundancy of RTK-transduced signaling in cancer cells and the broad role of RTK ligands in both innate and acquired resistance to kinase inhibitors. Clinical implications include the potential for HGF to contribute to resistance in *BRAF*-mutant melanoma and HER2-amplified breast cancer, and the use of RTK ligand biomarkers to inform treatment strategies.The study investigates the potential for growth-factor-driven resistance to anticancer kinase inhibitors. Using a panel of kinase-dependent human cancer cell lines, the researchers found that exposure to receptor tyrosine kinase (RTK) ligands can rescue cells from drug-induced growth inhibition. The most effective ligands were hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and neuregulin 1 (NRG1). These ligands reactivated survival signaling pathways, particularly the PI(3)K-AKT and MAPK pathways, despite the presence of the targeted kinase inhibitor. The findings highlight the extensive redundancy of RTK-transduced signaling in cancer cells and the broad role of RTK ligands in both innate and acquired resistance to kinase inhibitors. Clinical implications include the potential for HGF to contribute to resistance in *BRAF*-mutant melanoma and HER2-amplified breast cancer, and the use of RTK ligand biomarkers to inform treatment strategies.