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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    • "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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    • "Other biomarkers thought to be associated with addiction to oncogenic driver mutations and that are predictive of response to specific agents in NSCLC include BRAF, HER2, ROS1, FGFR1 and MET. KRAS is a driver mutation for which no specific targeted drug has yet been identified, and is thought to confer relative resistance to EGFR TKIs [25] [26] [27] [28] [29] [30] [31] [32]. More evidence is required to validate biomarkers such as PIK3CA, ERCC1, MSH2, TS, BRCA1 and RRM1 [33] [34]. "
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