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

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.

• Authors: Alexander Drilon, Romel Somwar, Jacob P Wagner, Nadeem A Vellore, Christopher A Eide, Matthew S Zabriskie, Maria E Arcila, Jaclyn F Hechtman, Lu Wang, Roger S Smith, Mark G Kris, Gregory J Riely, Brian J Druker, Thomas O'Hare, Marc Ladanyi, Monika A Davare
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 10 Pg. 2351-8 (05 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26673800 (Publication Type: Case Reports, Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Anilides
• Antigens, Differentiation, B-Lymphocyte
• Histocompatibility Antigens Class II
• Proto-Oncogene Proteins
• Pyrazoles
• Pyridines
• invariant chain
• cabozantinib
• Crizotinib
• Protein-Tyrosine Kinases
• ROS1 protein, human

Topics

• Adenocarcinoma (drug therapy, genetics)
• Adenocarcinoma of Lung
• Anilides (therapeutic use)
• Antigens, Differentiation, B-Lymphocyte (genetics)
• Cell Line, Tumor
• Clinical Trials, Phase II as Topic
• Crizotinib
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Histocompatibility Antigens Class II (genetics)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Middle Aged
• Mutation (drug effects, genetics)
• Oncogenes (drug effects, genetics)
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)
• Pyrazoles (therapeutic use)
• Pyridines (therapeutic use)