This study investigates the role of growth-factor-driven resistance in cancer cells treated with kinase inhibitors. It shows that many cancer cells can be rescued from drug sensitivity by exposure to receptor tyrosine kinase (RTK) ligands. The study used a panel of 41 human cancer cell lines with defined kinase dependencies to examine the effects of six widely expressed RTK ligands on drug response. The results showed that exposure to RTK ligands could rescue cells from drug-induced growth inhibition, with HGF, FGF, and NRG1 being the most effective. The study also found that ligand exposure could re-activate survival signaling pathways such as PI(3)K and MAPK, which may contribute to resistance. The findings suggest that RTK ligands play a broad role in both innate and acquired resistance to kinase inhibitors. The study also highlights the importance of RTK expression in tumor cells and the potential for using RTK ligands as biomarkers to inform treatment strategies. The study also found that HGF can confer resistance to BRAF inhibitors in BRAF-mutant melanoma cells, and that HGF levels in patients with BRAF-mutant melanoma are associated with worse clinical outcomes. The study also found that HGF can promote resistance to HER2 inhibitors in HER2-amplified breast cancer cells. Overall, the study highlights the extensive redundancy of RTK signaling in cancer cells and the potential for RTK ligands to be used in the development of more effective cancer therapies.This study investigates the role of growth-factor-driven resistance in cancer cells treated with kinase inhibitors. It shows that many cancer cells can be rescued from drug sensitivity by exposure to receptor tyrosine kinase (RTK) ligands. The study used a panel of 41 human cancer cell lines with defined kinase dependencies to examine the effects of six widely expressed RTK ligands on drug response. The results showed that exposure to RTK ligands could rescue cells from drug-induced growth inhibition, with HGF, FGF, and NRG1 being the most effective. The study also found that ligand exposure could re-activate survival signaling pathways such as PI(3)K and MAPK, which may contribute to resistance. The findings suggest that RTK ligands play a broad role in both innate and acquired resistance to kinase inhibitors. The study also highlights the importance of RTK expression in tumor cells and the potential for using RTK ligands as biomarkers to inform treatment strategies. The study also found that HGF can confer resistance to BRAF inhibitors in BRAF-mutant melanoma cells, and that HGF levels in patients with BRAF-mutant melanoma are associated with worse clinical outcomes. The study also found that HGF can promote resistance to HER2 inhibitors in HER2-amplified breast cancer cells. Overall, the study highlights the extensive redundancy of RTK signaling in cancer cells and the potential for RTK ligands to be used in the development of more effective cancer therapies.