The Oncogenic Lung Cancer Fusion Kinase CD74-ROS Activates a Novel Invasiveness Pathway through E-Syt1 Phosphorylation
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.
- SourceAvailable from: Wilfried E E Eberhardt
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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        . More evidence is required to validate biomarkers such as PIK3CA, ERCC1, MSH2, TS, BRCA1 and RRM1  . "
ABSTRACT: Advances in the management of non-small cell lung cancer (NSCLC) over the past 30 years have led to small increases in 5-year survival rates across Europe, though further improvements may require new treatment strategies. In order to improve efficiency and reduce the cost of development, future trials for new targeted agents in NSCLC should aim to recruit patients on the basis of tumour biology rather than clinical characteristics. However, identification of predictive biomarkers is required to maximise the benefits of new approaches and expedite the drug development process. Nevertheless, the NSCLC landscape is changing rapidly, and recent improvements in our understanding of the molecular biology of the disease will help in the identification of novel targeted agents as well as assisting in the development of personalised strategies for the numerous small subsets of defined NSCLC. Progress in imaging and treatment delivery is also likely to improve outcomes for patients with the disease. This article outlines recent progress in the treatment of NSCLC, identifies current challenges and describes proposals for improving the future management of the disease. It is hoped that implementation of some of these strategies will go some way to improving the outlook for patients with NSCLC.Lung cancer (Amsterdam, Netherlands) 09/2013; 82(3). DOI:10.1016/j.lungcan.2013.08.025 · 3.74 Impact Factor
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ABSTRACT: Protein phosphorylation plays key roles in the regulation of normal and cancer cells. It is a highly dynamic process. Protein kinases are the targets of several new cancer drugs and drug candidates. However, some of the main issues related to new drugs are how they function and the selection of those patients that will likely respond best to a particular treatment regime. There is an urgent need to understand and monitor kinase signalling pathways. Phosphoproteomics requires the enrichment of phosphorylated proteins or peptides from tissue or bodily fluids, and the application of technologies such as mass spectrometry (MS) to the identification and quantification of protein phosphorylation sites. As the field develops it will provide pharmacodynamic readouts of disease states and cellular drug responses in tumour samples. There have been a number of recent advances, but there are still technical hurdles and bioinformatics challenges that need to be addressed.Clinical and Translational Oncology 07/2009; 11(6):356-62. · 2.08 Impact Factor
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ABSTRACT: Phosphorylation is one of the most common post translational modifications (PTM), participating in a large number of processes to regulate cellular functions. Phosphorylation is also one of the key factors in the origin and development of cancer. The rapid development of mass spectrometric-based phosphoproteomic technologies has made it possible for high-throughput identification and quantification of phosphorylation events. In this review, we provide a general introduction and summary of the achievements made in mass spectrometry based phosphoproteomic research, including the approaches for phosphopeptide identification and quantification, as well as instrumentation and data interpretation methods. We also review some discoveries in cancer research made possible by phosphoproteomic analysis technologies.12/2012; 7(6). DOI:10.1007/s11515-012-2022-4