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Clin Cancer Res. 2016 May 15;22(10):2351-8. doi: 10.1158/1078-0432.CCR-15-2013. Epub 2015 Dec 16.

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

Author information

1
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York. drilona@mskcc.org davarem@ohsu.edu.
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Knight Cancer Institute and Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.
4
Huntsman Cancer Institute and Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah.
5
Knight Cancer Institute and Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon. Howard Hughes Medical Institute, Portland, Oregon.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Knight Cancer Institute and Department of Pediatrics, Oregon Health & Science University, Portland, Oregon. drilona@mskcc.org davarem@ohsu.edu.

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 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. Clin Cancer Res; 22(10); 2351-8. ©2015 AACR.

PMID:
26673800
PMCID:
PMC4867287
DOI:
10.1158/1078-0432.CCR-15-2013
[Indexed for MEDLINE]
Free PMC Article

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