The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation

Molecular Oncology Research Institute, Department of Neurosurgery, Tufts University School of Medicine, Boston, MA 02111, USA.
Cancer Research (Impact Factor: 9.33). 06/2012; 72(15):3764-74. DOI: 10.1158/0008-5472.CAN-11-3990
Source: PubMed


Patients with lung cancer often present with metastatic disease and therefore have a very poor prognosis. The recent discovery of several novel ROS receptor tyrosine kinase molecular alterations in non-small cell lung cancer (NSCLC) presents a therapeutic opportunity for the development of new targeted treatment strategies. Here, we report that the NSCLC-derived fusion CD74-ROS, which accounts for 30% of all ROS fusion kinases in NSCLC, is an active and oncogenic tyrosine kinase. We found that CD74-ROS-expressing cells were highly invasive in vitro and metastatic in vivo. Pharmacologic inhibition of CD74-ROS kinase activity reversed its transforming capacity by attenuating downstream signaling networks. Using quantitative phosphoproteomics, we uncovered a mechanism by which CD74-ROS activates a novel pathway driving cell invasion. Expression of CD74-ROS resulted in the phosphorylation of the extended synaptotagmin-like protein E-Syt1. Elimination of E-Syt1 expression drastically reduced invasiveness both in vitro and in vivo without modifying the oncogenic activity of CD74-ROS. Furthermore, expression of CD74-ROS in noninvasive NSCLC cell lines readily conferred invasive properties that paralleled the acquisition of E-Syt1 phosphorylation. Taken together, our findings indicate that E-Syt1 is a mediator of cancer cell invasion and molecularly define ROS fusion kinases as therapeutic targets in the treatment of NSCLC.

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Article: The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation

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    • "Several studies have demonstrated that some of these fusions induce anchorage-independent growth, foci formation, and tumorigenicity in fibroblast models (Charest et al., 2003a; Gu et al., 2011; Jun et al., 2012); in particular, the FIG–ROS1 fusion gene has been shown to promote astrocytoma formation in a murine model, while EZR– ROS1 fusion gene promotes lung adenocarcinoma "
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    • "Only seven articles in published medical literature mention anything at all about this relatively obscure protein. However, recent studies show E-syt1 to be of potentially great importance, as one study from 2012 discovered that the Non Small Cell Lung Carcinoma derived fusion kinase CD74-ROS,26 which for NSCLC comprises 30% of all ROS fusion kinases, is an active and oncogenic tyrosine kinase that when expressed results in phosphorylation of extended synaptotagmin-like protein (E-Syt1); the investigators found that elimination of E-Syt1 expression drastically reduced tumor invasiveness. A subsequent study published in 2013 emphasizes a key role for E-syt1 in the dynamics of endoplasmic reticulum (ER)-plasma membrane (PM) junctional interactions.27 "
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