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Deprecated: Implicit conversion from float 219.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell+Rep 2017 ; 20 (10): 2368-83 Nephropedia Template TP
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KIF5B-RET Oncoprotein Signals Through A Multi-Kinase Signaling Hub #MMPMID28877471
Das TK; Cagan RL
Cell Rep 2017[Sep]; 20 (10): 2368-83 PMID28877471show ga
Gene fusions are increasingly recognized as important cancer drivers. KIF5B-RET gene was recently identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation including invadopodia-like processes. Through a combination of genetic and biochemical studies we demonstrate that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB vesicle-dependent RET-SRC-EGFR-FGFR ?signaling hub?. We demonstrate that drugs designed to inhibit RET alone work poorly in KIF5B-RET-transformed cells. However, combining the RET inhibitor sorafenib with drugs that target EGFR or microtubules or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility in exploring the full biology of fusions to identify rational therapeutic strategies.