KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Tirtha Kamal Das, Ross Leigh Cagan
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.

Graphical abstract

Teaser

Das and Cagan find that each portion of the KIF5B-RET fusion oncoprotein recruits different components to assemble a multi-kinase oncogenic signaling hub that promotes invadopodia formation. This suggests that multiple kinase components of this KIF5B-RET hub need to be simultaneously targeted therapeutically.


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