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A novel approach to detect resistance mechanisms reveals FGR as a factor mediating HDAC inhibitor SAHA resistance in B-cell lymphoma

  • Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are not commonly used in clinical practice for treatment of B-cell lymphomas, although a subset of patients with refractory or relapsed B-cell lymphoma achieved partial or complete remissions. Therefore, the purpose of this study was to identify molecular features that predict the response of B-cell lymphomas to SAHA treatment. We designed an integrative approach combining drug efficacy testing with exome and captured target analysis (DETECT). In this study, we tested SAHA sensitivity in 26 B-cell lymphoma cell lines and determined SAHA-interacting proteins in SAHA resistant and sensitive cell lines employing a SAHA capture compound (CC) and mass spectrometry (CCMS). In addition, we performed exome mutation analysis. Candidate validation was done by expression analysis and knock-out experiments. An integrated network analysis revealed that the Src tyrosine kinase Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog (FGR) is associated with SAHA resistance. FGR was specifically captured by the SAHA-CC in resistant cells. In line with this observation, we found that FGR expression was significantly higher in SAHA resistant cell lines. As functional proof, CRISPR/Cas9 mediated FGR knock-out in resistant cells increased SAHA sensitivity. In silico analysis of B-cell lymphoma samples (n = 1200) showed a wide range of FGR expression indicating that FGR expression might help to stratify patients, which clinically benefit from SAHA therapy. In conclusion, our comprehensive analysis of SAHA-interacting proteins highlights FGR as a factor involved in SAHA resistance in B-cell lymphoma.

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Metadaten
Document Type:Article
Language:English
Parent Title (English):Mol Oncol. (Molecular Oncology)
Volume:10
Issue:8
First Page:1232
Last Page:1244
ISSN:1574-7891
DOI:https://doi.org/10.1016/j.molonc.2016.06.001
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27324824
Publisher:FEBS Press
Date of first publication:2016/06/09
Tag:B-cell lymphoma; Drug resistance; FGR; HDAC inhibitor; SAHA
Departments, institutes and facilities:Fachbereich Informatik
Institut für funktionale Gen-Analytik (IfGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2016/06/23