A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer
- 12 May 2016
- journal article
- case report
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 22 (10), 2351-2358
- https://doi.org/10.1158/1078-0432.ccr-15-2013
Abstract
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 ROS1D2033N mutation in a patient with CD74-ROS1–rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib resistance of CD74-ROS1D2033N was functionally evaluated using cell-based assays and structural modeling. Results: In biochemical and cell-based assays, the CD74-ROS1D2033N 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. Clin Cancer Res; 22(10); 2351–8. ©2015 AACR.Keywords
Other Versions
This publication has 30 references indexed in Scilit:
- Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)The Journal of Molecular Diagnostics, 2015
- Crizotinib Therapy for Advanced Lung Adenocarcinoma and a ROS1 Rearrangement: Results From the EUROS1 CohortJournal of Clinical Oncology, 2015
- Detecting and targetting oncogenic fusion proteins in the genomic eraBiology of the Cell, 2015
- Cabozantinib Overcomes Crizotinib Resistance in ROS1 Fusion–Positive CancerClinical Cancer Research, 2015
- Crizotinib in ROS1-Rearranged Non–Small-Cell Lung CancerThe New England Journal of Medicine, 2014
- Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1The New England Journal of Medicine, 2013
- Analysis of Receptor Tyrosine Kinase ROS1-Positive Tumors in Non–Small Cell Lung Cancer: Identification of a FIG-ROS1 FusionClinical Cancer Research, 2012
- ROS1 Rearrangements Define a Unique Molecular Class of Lung CancersJournal of Clinical Oncology, 2012
- RET, ROS1 and ALK fusions in lung cancerNature Medicine, 2012
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal of Cancer, 2009