title: Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma.
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 RETV804Lmutation and vandetanib-resistant-RETG810Amutation. 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-RETG810Amutant 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 RETG810Amutation and identifies lenvatinib and ponatinib as the secondary drugs to overcome this vandetanib resistance mechanism. Mol Cancer Ther; 15(10); 2521-9. ©2016 AACR.
authors: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Qingling
authors: Q
authors: Huang
authors: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Valentina E
authors: VE
authors: Schneeberger
authors: Small Animal Modeling and Imaging Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Noreen
authors: N
authors: Luetteke
authors: Transgenic and Gene Targeting Core, Georgia State University, Atlanta, Georgia.
authors: Chengliu
authors: C
authors: Jin
authors: Small Animal Modeling and Imaging Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Roha
authors: R
authors: Afzal
authors: Small Animal Modeling and Imaging Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Mikalai M
authors: MM
authors: Budzevich
authors: Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Rikesh J
authors: RJ
authors: Makanji
authors: Small Animal Modeling and Imaging Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Gary V
authors: GV
authors: Martinez
authors: Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors: Tao
authors: T
authors: Shen
authors: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors: Lichao
authors: L
authors: Zhao
authors: Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors: Kar-Ming
authors: KM
authors: Fung
authors: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Department of Oncology Sciences, University of South Florida College of Medicine, Tampa, Florida.
authors: Eric B
authors: EB
authors: Haura
authors: Department of Oncology Sciences, University of South Florida College of Medicine, Tampa, Florida. Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Domenico
authors: D
authors: Coppola
authors: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Oncology Sciences, University of South Florida College of Medicine, Tampa, Florida. jie-wu@ouhsc.edu.
authors: Jie
authors: J
authors: Wu
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001706:Biopsy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D019076:Transgenes; D055114:X-Ray Microtomography
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C573239:KIF5B-RET fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib