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

Abstract

Summary 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.

A novel KIF5B-ALK fusion in a child with an atypical central nervous system inflammatory myofibroblastic tumour

“…The presence of this ALK fusion may suggest that recurrences could be treated with ALK inhibitors such as crizotinib and ceritinib. However, there is evidence that the N-terminus domain of KIF5B fusion proteins can activate receptor tyrosine kinases (RTKs) independently of the C-terminus kinase domain in KIF5B-RET fusions, indicating a potential need to combine epidermal growth factor receptor inhibitors with ALK inhibitors in KIF5B-ALK fusions 3. Overall, our case highlights a novel ALK fusion with KIF5B in a rare inflammatory atypical myofibroblastic tumour of the CNS.…”

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105

“…This was initially demonstrated in Drosophila models with CCDC6-RET and NCOA4-RET when these fusion genes were expressed in the epithelia during development (16). A study also using Drosophila models in addition to engineered human bronchial epithelial cells further revealed that the kinesin domain of KIF5B and the kinase domain of RET act together to form a multikinase (RET/EGFR/FGFR/SRC) signaling hub (17). This suggests that, rather than targeting RET alone, multiple kinase components of the KIF5B-RET signaling hub may need to be simultaneously targeted for optimal effect.…”

Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring Activating RET Alterations and Oncogenic Signaling Pathway Aberrations

“…However, the fact that no KIF5B-RET fusion arose as a mechanism of resistance in this series suggests emergent KIF5B-RET fusions may not be tolerated in the presence of anti-EGFR TKI and/or that loss of CCDC6 or NCOA4 affords a particular survival advantage to tumors exposed to an EGFR TKI. In a Drosophila model, KIF5B-RET fusions (particularly the motor domain that is unique to KIF5B relative to the other fusion partners) are highly reliant on EGFR signaling to promote enhanced cell growth, more so than CCDC6-RET or NCOA4-RET fusions (50). There may be important cell biology differences based on the RET fusion partner.…”