The emergence of resistance to targeted therapy is a recurrent clinical challenge and requires development and validation of secondary agents with improved activity. Accompanied by experimental cell-based and structural validation, this report of a near complete response to cabozantinib in a ROS1-rearranged lung adenocarcinoma patient with acquired resistance to crizotinib mediated by a novel CD74-ROS1 D2033N solvent-front mutation provides the first clinical example of crizotinib resistance overcome by targeted therapy in a ROS1-rearranged malignancy.
