A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer

作者：Drilon Alexander^*; Somwar Romel; Wagner Jacob P; Vellore Nadeem A; Eide Christopher A; Zabriskie Matthew S; Arcila Maria E; Hechtman Jaclyn F; Wang Lu; Smith Roger S; Kris Mark G; Riely Gregory J; Druker Brian J; O'Hare Thomas; Ladanyi Marc; Davare Monika A^*

来源：Clinical Cancer Research, 2016, 22(10): 2351-2358.

DOI：10.1158/1078-0432.CCR-15-2013

Purpose: Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential.
Experimental Design: We report the discovery of a novel, solvent-front ROS1(D2033N) mutation in a patient with CD74-ROS1-rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib resistance of CD74-ROS1(D2033N) was functionally evaluated using cell-based assays and structural modeling.
Results: In biochemical and cell-based assays, the CD74-ROS1(D2033N) mutant demonstrated significantly decreased sensitivity to crizotinib. Molecular dynamics simulation revealed compromised crizotinib binding due to drastic changes in the electrostatic interaction between the D2033 residue and crizotinib and reorientation of neighboring residues. In contrast, cabozantinib binding was unaffected by the D2033N substitution, and inhibitory potency against the mutant was retained. Notably, cabozantinib treatment resulted in a rapid clinical and near-complete radiographic response in this patient.
Conclusions: These results provide the first example of successful therapeutic intervention with targeted therapy to overcome crizotinib resistance in a ROS1-rearranged cancer.

• 出版日期2016-5-15