Oncotarget

Research Papers:

Whole exome sequencing identifies mTOR and KEAP1 as potential targets for radiosensitization of HNSCC cells refractory to EGFR and β1 integrin inhibition

Erik Klapproth, Ellen Dickreuter, Falk Zakrzewski, Michael Seifert, Andreas Petzold, Andreas Dahl, Evelin Schröck, Barbara Klink and Nils Cordes _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2018; 9:18099-18114. https://doi.org/10.18632/oncotarget.24266

Metrics: PDF 1928 views  |   HTML 2843 views  |   ?  


Abstract

Erik Klapproth1, Ellen Dickreuter1, Falk Zakrzewski2,3,4, Michael Seifert5,6, Andreas Petzold7, Andreas Dahl7, Evelin Schröck2,3,4,8, Barbara Klink2,3,4,7,8 and Nils Cordes1,2,3,9,10

1OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany

2German Cancer Consortium (DKTK), Dresden 01307, Germany

3German Cancer Research Center (DKFZ), Dresden partner site, Heidelberg 69120, Germany

4Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden 01307, Germany

5Institute for Medical Informatics and Biometry (IMB), Technische Universität Dresden, Dresden 01307, Germany

6National Center for Tumor Diseases (NCT), Dresden 01307, Germany

7Deep Sequencing Group, BIOTEChnology Center, Technische Universität Dresden, Dresden 01307, Germany

8Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany

9Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany

10Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Dresden 01328, Germany

Correspondence to:

Nils Cordes, email: [email protected]

Keywords: beta1 integrin; EGFR; Exome; ionizing radiation; HNSCC

Received: August 22, 2016     Accepted: January 09, 2018     Published: April 06, 2018

ABSTRACT

Intrinsic and acquired resistances are major obstacles in cancer therapy. Genetic characterization is commonly used to identify predictive or prognostic biomarker signatures and potential cancer targets in samples from therapy-naïve patients. By far less common are such investigations to identify specific, predictive and/or prognostic gene signatures in patients or cancer cells refractory to a specific molecular-targeted intervention. This, however, might have a great value to foster the development of tailored, personalized cancer therapy. Based on our identification of a differential radiosensitization by single and combined β1 integrin (AIIB2) and EGFR (Cetuximab) targeting in more physiological, three-dimensional head and neck squamous cell carcinoma (HNSCC) cell cultures, we performed comparative whole exome sequencing, phosphoproteome analyses and RNAi knockdown screens in responder and non-responder cell lines. We found a higher rate of gene mutations with putative protein-changing characteristics in non-responders and different mutational profiles of responders and non-responders. These profiles allow stratification of HNSCC patients and identification of potential targets to address treatment resistance. Consecutively, pharmacological inhibition of mTOR and KEAP1 effectively diminished non-responder insusceptibility to β1 integrin and EGFR targeting for radiosensitization. Our data pinpoint the added value of genetic biomarker identification after selection for cancer subgroup responsiveness to targeted therapies.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 24266