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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / genetics*
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Antigens, Differentiation, B-Lymphocyte / physiology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / metabolism
  • Histocompatibility Antigens Class II / physiology
  • Humans
  • Intracellular Calcium-Sensing Proteins / metabolism*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness / genetics
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Oncogene Proteins, Fusion / physiology*
  • Phosphorylation / genetics
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • Rats
  • Signal Transduction / genetics

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Histocompatibility Antigens Class II
  • Intracellular Calcium-Sensing Proteins
  • Membrane Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • invariant chain
  • Protein-Tyrosine Kinases
  • ROS1 protein, human