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Preclinical Modeling of KIF5B–RET Fusion Lung Adenocarcinoma

Preclinical Modeling of KIF5B–RET Fusion Lung Adenocarcinoma

Authors :
Tao Shen
Mikalai M. Budzevich
Domenico Coppola
Eric B. Haura
Chengliu Jin
Rikesh Makanji
Gary V. Martinez
Roha Afzal
Valentina E. Schneeberger
Lichao Zhao
Kar Ming Fung
Jie Wu
Noreen Luetteke
Qingling Huang
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.

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