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

Research output: Contribution to journalResearch articleContributedpeer-review



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 nonresponder cell lines. We found a higher rate of gene mutations with putative proteinchanging 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.


Original languageEnglish
Pages (from-to)18099-18114
Number of pages16
Issue number26
Publication statusPublished - 1 Apr 2018

External IDs

ORCID /0000-0001-9599-8632/work/142241747
ORCID /0000-0001-5684-629X/work/146646159
ORCID /0000-0002-2844-053X/work/153110479


Sustainable Development Goals

ASJC Scopus subject areas


  • Beta1 integrin, EGFR, Exome, HNSCC, Ionizing radiation

Library keywords