Article ; Online: KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub.
2017 Volume 20, Issue 10, Page(s) 2368–2383
Abstract: Gene fusions are increasingly recognized as important cancer drivers. The KIF5B-RET gene has been identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of ... ...
| Abstract | Gene fusions are increasingly recognized as important cancer drivers. The KIF5B-RET gene has been 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. The 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, microtubules, or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility of exploring the full biology of fusions to identify rational therapeutic strategies. |
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| MeSH term(s) | Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma of Lung ; Animals ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Cell Line, Tumor ; Drosophila ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; Tissue Culture Techniques ; Translocation, Genetic/genetics |
| Chemical Substances | KIF5B-RET fusion protein, human ; Oncogene Proteins, Fusion |
| Language | English |
| Publishing date | 2017-09-06 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 2649101-1 |
| ISSN | 2211-1247 ; 2211-1247 |
| ISSN (online) | 2211-1247 |
| ISSN | 2211-1247 |
| DOI | 10.1016/j.celrep.2017.08.037 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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