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Cancer Res. 2012 Aug 1;72(15):3764-74. doi: 10.1158/0008-5472.CAN-11-3990. Epub 2012 Jun 1.

The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation.

Author information

1
Molecular Oncology Research Institute, Department of Neurosurgery, Tufts University School of Medicine, Boston, MA 02111, USA.

Abstract

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.

PMID:
22659450
PMCID:
PMC3753671
DOI:
10.1158/0008-5472.CAN-11-3990
[Indexed for MEDLINE]
Free PMC Article

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