@article{Anti-metastatic:1725,
      recid = {1725},
      author = {Yesilkanal, Ali Ekrem},
      title = {Discovery of Anti-metastatic Therapies Guided by the  Physiological Suppressor Raf Kinase Inhibitory Protein},
      publisher = {The University of Chicago},
      school = {Ph.D.},
      address = {2019-03},
      pages = {132},
      abstract = {Metastatic progression of tumors is the major cause of  death in patients with triple neg-

ative breast cancer  (TNBC). However, since metastasis is a multi-step process,  unraveling

its complexity is a major challenge. One  eective way of tackling this question is to study

natural  blockers of the metastatic process, metastasis suppressors,  and identify the mecha-

nisms by which they regulate  metastasis. Raf kinase inhibitory protein (RKIP, also  known

as PEBP1), a protein that regulates kinase activity,  is a physiological suppressor of TNBC

metastasis. Although  RKIP inhibits the activity of Raf-1, other kinase targets  of RKIP in

tumors are not known. To address this question,  we used a mass spectrometry approach

involving  inhibitor-conjugated beads to identify kinases that are  down-regulated by RKIP in

human TNBC xenograft tumors. Our  results identied a network of stress kinases targeted

by  RKIP, including kinases that have not been previously  reported as RKIP targets. By

using a high-throughput  invasion assay, we developed a low-dose multi-drug cocktail  of ki-

nase inhibitors targeting stress MAP kinases p38,  JNK, MLK, and MEK. This combination

treatment mimicked  RKIP's anti-metastatic role in cultured cell, as well as  xenograft and

syngeneic models of TNBC. In order to  unravel the eect of this stress network on metastatic

gene  expression, we conducted an RNA-seq analysis comparing  metastatic xenograft tumors

to non-metastatic  RKIP-overexpressing tumors. Genes downregulated by RKIP in  these

tumors were enriched in motility and invasion  related gene sets, and their expression was

induced under  stress conditions. Several of these genes were directly  regulated by BACH1, a

pro-metastatic factor targeted by  RKIP. Interestingly, the same genes were negatively  corre-

lated with RKIP expression across multiple TCGA  cancer types and with other metastasis

suppressor genes  within the breast cancer cohort, highlighting the clinical  relevance of the

RKIP-network. Elucidating RKIP function  at a systems level reveals the interplay between

key  metastatic signaling cascades, particularly in relation to  cell motility and invasion. Our

ndings suggest that a  low-dose, multi-drug combination therapy that targets a  network of

stress kinases is a viable anti-metastatic  therapy for TNBC patients.},
      url = {http://knowledge.uchicago.edu/record/1725},
      doi = {https://doi.org/10.6082/uchicago.1725},
}