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Preclinical Modeling of KIF5B–RET Fusion Lung Adenocarcinoma
Preclinical Modeling of KIF5B–RET Fusion Lung Adenocarcinoma
- Source :
- Molecular Cancer Therapeutics. 15:2521-2529
- Publication Year :
- 2016
- Publisher :
- American Association for Cancer Research (AACR), 2016.
-
Abstract
- RET fusions have been found in lung adenocarcinoma, of which KIF5B–RET is the most prevalent. We established inducible KIF5B-RET transgenic mice and KIF5B–RET-dependent cell lines for preclinical modeling of KIF5B–RET-associated lung adenocarcinoma. Doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. Tumors regressed upon suppression of KIF5B–RET expression. By culturing KIF5B–RET-dependent BaF3 (B/KR) cells with increasing concentrations of cabozantinib or vandetanib, we identified cabozantinib-resistant RETV804L mutation and vandetanib-resistant-RETG810A mutation. Among cabozantinib, lenvatinib, ponatinib, and vandetanib, ponatinib was identified as the most potent inhibitor against KIF5B–RET and its drug-resistant mutants. Interestingly, the vandetanib-resistant KIF5B-RETG810A mutant displayed gain-of-sensitivity (GOS) to ponatinib and lenvatinib. Treatment of doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice with ponatinib effectively induced tumor regression. These results indicate that KIF5B-RET–associated lung tumors are addicted to the fusion oncogene and ponatinib is the most effective inhibitor for targeting KIF5B–RET in lung adenocarcinoma. Moreover, this study finds a novel vandetanib-resistant RETG810A mutation and identifies lenvatinib and ponatinib as the secondary drugs to overcome this vandetanib resistance mechanism. Mol Cancer Ther; 15(10); 2521–9. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Lung Neoplasms
Oncogene Proteins, Fusion
endocrine system diseases
Biopsy
Gene Expression
Vandetanib
Mice
chemistry.chemical_compound
0302 clinical medicine
Gene Order
Transgenes
Ponatinib
Imidazoles
Immunohistochemistry
Magnetic Resonance Imaging
Pyridazines
Cell Transformation, Neoplastic
Oncology
030220 oncology & carcinogenesis
Adenocarcinoma
Lenvatinib
medicine.drug
congenital, hereditary, and neonatal diseases and abnormalities
endocrine system
Cabozantinib
Genetic Vectors
Adenocarcinoma of Lung
Antineoplastic Agents
Mice, Transgenic
Article
03 medical and health sciences
Cell Line, Tumor
medicine
Animals
Humans
Protein Kinase Inhibitors
neoplasms
Oncogene
business.industry
Cancer
X-Ray Microtomography
medicine.disease
Disease Models, Animal
030104 developmental biology
chemistry
Immunology
Cancer research
business
Subjects
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....d1a5d1a665de9525c84e3110b5c9a47f
- Full Text :
- https://doi.org/10.1158/1535-7163.mct-16-0258