Dataset Information

Whole exome sequencing identifies mTOR and KEAP1 as potential targets for radiosensitization of HNSCC cells refractory to EGFR and ?1 integrin inhibition.

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 ?1 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 ?1 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.

SUBMITTER: Klapproth E

PROVIDER: S-EPMC5915060 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Klapproth Erik E Dickreuter Ellen E Zakrzewski Falk F Seifert Michael M Petzold Andreas A Dahl Andreas A Schröck Evelin E Klink Barbara B Cordes Nils N

Oncotarget 20180406 26

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 develop ...[more]

PMID: 29719593

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Project description:We previously described the novel zinc finger protein ZKSCAN3 as a new "driver" of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif. In expression profiling, 204 genes were induced 2-29-fold, and 76 genes reduced 2-5-fold by ZKSCAN3. To enrich for direct targets, we eliminated genes under-represented (<3) for the ZKSCAN3 binding motif (identified by CAST-ing) in 2 kilobases of regulatory sequence. Up-regulated putative downstream targets included genes contributing to growth (c-Met-related tyrosine kinase (MST1R), MEK2; the guanine nucleotide exchanger RasGRP2, insulin-like growth factor-2, integrin beta 4), cell migration (MST1R), angiogenesis (vascular endothelial growth factor), and proteolysis (MMP26; cathepsin D; PRSS3 (protease serine 3)). We pursued integrin beta 4 (induced up to 6-fold) as a candidate target because it promotes breast cancer tumorigenicity and stimulates phosphatidyl 3-kinase implicated in colorectal cancer progression. ZKSCAN3 overexpression/silencing modulated integrin beta 4 expression, confirming the array analysis. Moreover, ZKSCAN3 bound to the integrin beta 4 promoter in vitro and in vivo, and the integrin beta 4-derived ZKSCAN3 motif fused upstream of a tk-Luc reporter conferred ZKSCAN3 sensitivity. Integrin beta 4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation. We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin beta 4.

Dataset Information

Whole exome sequencing identifies mTOR and KEAP1 as potential targets for radiosensitization of HNSCC cells refractory to EGFR and ?1 integrin inhibition.

Publications

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

Similar Datasets

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