Here we show that a CCDC6-RET fusion product, a driver and therapeutic target in lung and thyroid cancers, is a highly active dimeric kinase in solution. Time-resolved mass spectrometry analysis together with a robust biochemical and biophysical characterization reveal the autophosphorylation kinetics and nucleotide dependency. Structural analyses together with cross-linking mass spectrometry data provided clear insights into the mechanism of autoactivation.