G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells.

Background: The gene of the Epidermal growth factor receptor (EGFR) is one of the most frequently altered genes in glioblastoma (GBM), with deletions of exons 2-7 (EGFRvIII) being amongst the most common genomic mutations. EGFRvIII is heterogeneously expressed in GBM. We already showed that EGFRvIII expression has an impact on chemosensitivity, replication stress, and the DNA damage response.

Increased replication stress and R-loop accumulation in EGFRvIII-expressing glioblastoma present new therapeutic opportunities.

Background: The oncogene epidermal growth factor receptor variant III (EGFRvIII) is expressed in approximately one-third of all glioblastomas (GBMs). So far it is not clear if EGFRvIII expression induces replication stress in GBM cells, which might serve as a therapeutical target.

Methods: Isogenetic EGFRvIII- and EGFRvIII+ cell lines with endogenous EGFRvIII expression were used.

Exploiting Chromosomal Instability of PTEN-Deficient Triple-Negative Breast Cancer Cell Lines for the Sensitization against PARP1 Inhibition in a Replication-Dependent Manner.

Chromosomal instability (CIN) is an emerging hallmark of cancer and its role in therapeutic responses has been increasingly attracting the attention of the research community. To target the vulnerability of tumors with high CIN, it is important to identify the genes and mechanisms involved in the maintenance of CIN. In our work, we recognize the tumor suppressor gene Phosphatase and Tensin homolog ( as a potential gene causing CIN in triple-negative breast cancer (TNBC) and show that TNBC with low expression levels of PTEN can be sensitized for the treatment with poly-(ADP-ribose)-polymerase 1 (PARP1) inhibitors, independent of Breast Cancer (BRCA) mutations or a BRCA-like phenotype.

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer.

Chromosomal instability not only has a negative effect on survival in triple-negative breast cancer, but also on the well treatable subgroup of luminal A tumors. This suggests a general mechanism independent of subtypes. Increased chromosomal instability (CIN) in triple-negative breast cancer (TNBC) is attributed to a defect in the DNA repair pathway homologous recombination.

Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests.

The increase in cellular radiosensitivity by EGF receptor (EGFR) inhibition has been shown to be attributable to the induction of a G1-arrest in p53-proficient cells. Because EGFR targeting in combination with radiotherapy is used to treat head and neck squamous cell carcinomas (HNSCC) which are predominantly p53 mutated, we tested the effects of EGFR targeting on cellular radiosensitivity, proliferation, apoptosis, DNA repair and cell cycle control using a large panel of HNSCC cell lines. In these experiments EGFR targeting inhibited signal transduction, blocked proliferation and induced radiosensitization but only in some cell lines and only under normal (pre-plating) conditions.

Quantitative proteomics unveiled: Regulation of DNA double strand break repair by EGFR involves PARP1.

Background: EGFR inhibition blocks DNA double strand break (DSB) repair but the detailed mechanisms are still unclear. We asked whether EGFR inhibition blocks DSB repair by reducing the X-ray-induced phosphorylation of repair proteins using a phosphoproteomic approach.

Materials And Methods: Using UT-SCC5 and SAS head and neck cancer cells we established a differential phosphoproteomic approach for quantitative analysis of DNA repair proteins by stable isotope labeling with amino acids.