A5025948733- Biochemical and Molecular Research
- Microtubule and mitosis dynamics
- Protein Degradation and Inhibitors
- DNA Repair Mechanisms
- Ubiquitin and proteasome pathways
- HER2/EGFR in Cancer Research
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Peptidase Inhibition and Analysis
- Genetic factors in colorectal cancer
- RNA Research and Splicing
- Cancer Treatment and Pharmacology
- RNA modifications and cancer
- Nuclear Structure and Function
- RNA and protein synthesis mechanisms
- Colorectal Cancer Treatments and Studies
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Fungal and yeast genetics research
- Mitochondrial Function and Pathology
- Bioinformatics and Genomic Networks
- Single-cell and spatial transcriptomics
- Cancer-related Molecular Pathways
- Immunotherapy and Immune Responses
- Cancer-related gene regulation
Boehringer Ingelheim (Austria)
2019-2024
Boehringer Ingelheim (Germany)
2019-2021
Research Institute of Molecular Pathology
2005-2020
Vienna Biocenter
2019
University of California, San Francisco
2015-2016
Howard Hughes Medical Institute
2015-2016
Max Planck Institute of Molecular Cell Biology and Genetics
2007-2012
Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing RNA], a method quantification newly synthesized messenger RNAs (mRNAs), with pharmacological chemical-genetic perturbation order define functions two transcriptional hubs cancer, BRD4 MYC, interrogate responses BET bromodomain inhibitors (BETis). found that acts as general coactivator...
During meiosis, two rounds of chromosome segregation after a single round DNA replication produce haploid gametes from diploid precursors. At meiosis I, maternal and paternal kinetochores are pulled toward opposite poles, chiasmata holding bivalent chromosomes together resolved by cleavage cohesin's alpha-kleisin subunit (Rec8) along arms. This creates dyad containing pair chromatids joined solely cohesin at centromeres that had resisted cleavage. The discovery centromeric Rec8 is protected...
The assembly of mitotic chromosomes is controlled by condensin complexes. In vertebrates, I binds to chromatin in prometaphase, confers rigidity and enables the release cohesin complexes from chromosome arms, whereas II associates with prophase promotes their condensation. Both are essential for segregation anaphase. Although association condensins important chromosomes, it poorly understood how this process controlled. Here we show that kinase Aurora B regulates I, but not interaction...
The transcription cycle of RNA polymerase II (Pol II) is regulated at discrete transition points by cyclin-dependent kinases (CDKs). Positive elongation factor b (P-TEFb), a complex Cdk9 and cyclin T1, promotes release paused Pol into elongation, but the precise mechanisms targets action remain largely unknown. Here, chemical genetic strategy, we identified ∼100 putative substrates human P-TEFb, which were enriched for proteins implicated in catabolism. Among processing factors...
Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability microsatellite instability-high (MSI-H) MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability MSI-H but not stable (MSS) colorectal lines. In...
<p>PRISM platform–based high-throughput screen with more than 900 cancer cell lines shows sensitivity of BI-2493 across a wide range <i>KRAS</i>-altered lines. <b>A,</b> Sensitivity data 801 after quality control are shown (Supplementary Table S1). Cancer ranked from the highest (left) to lowest (right) using measure 1 − AUC (area under dose–response curve). Red bars highlight lines, including <i>KRAS</i> mutations (point mutations, insertions, and...
<p><i>KRAS</i> WT–amplified tumors are enriched in gastroesophageal cancers. <b>A,</b> TCGA cohort was queried for <i>KRAS</i> patients. Frequency of patients is shown, stratified by different thresholds relative CNs. Only the top 10 altered cancer types shown CN 2 to 3. <b>B,</b> Stratified Cox regression grouped thresholds. For each analysis, were a variable interest (e.g., > 7) and compared with all other OR plots show log scale...
<div>Abstract<p>KRAS<sup>G12C</sup> selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other <i>KRAS</i>-mutant alleles in patients with cancer. We report that <i>KRAS</i> wild-type (WT)–amplified tumor models are sensitive to treatment the small-molecule KRAS inhibitors BI-2493 BI-2865. These pan-KRAS directly target “OFF” state result potent antitumor activity preclinical cancers driven by KRAS-mutant...
<p>Supplementary Figure 1: Cellular sensitivity to BI-2493 integrated with CRISPR and RNAi gene dependency data. (Top) CRISPR: Drug-target associations show selectivity of for KRAS but not HRAS NRAS. Panel left, mid right effect (or dependency) scores derived from Chronos KRAS, NRAS, respectively on the x-axis. A low score indicates that a cell line is likely depend given gene. equal or close 0 genes are non-essential, whereas -1 defined as median all common essential commonly used...
<p>Supplementary Figure 9: BI-2493 and BI-2865 treatment induces cell cycle arrest apoptosis in KRAS wild-type amplified cancer lines. (A) Upper panel: Representative flow blots of states determined by EdU incorporation into newly synthesized DNA total content staining FxCycle indicated lines treated for 48 h with DMSO (mock), 3 µM BI-2493, 0.3 trametinib. Cells were pre-gated based on scattering properties content. Numbers indicate frequency parent population. Lower Impact or...
<p>Supplementary Figure 6: Relationship between KRAS wild-type amplification and oncogenic activity in TCGA patient data. RAS activation signatures MPAS (3), RAS_addiction Ras84 (1). Enrichment scores were estimated using single sample enrichment (ssGSEA) A one-sided Wilcox-test was used to test for significance relative copy number of 2-7 or >7.</p>
<p><i>KRAS</i> WT–amplified cancer cell lines are sensitive to pan-KRAS inhibitors BI-2493 and BI-2865. <b>A,</b> Cell tested for sensitivity were ranked according <i>KRAS</i> WT relative CN. Tumor of origin gene expression [log<sub>2</sub>(TPM + 1)] indicated. <b>B, </b><i>In vitro</i> shown in <b>A</b> BI-2493, BI-2865, trametinib (<i>n</i> = 3, means ± SD). Control lines, with CN < 7,...
<p>Supplementary Figure 7. Gastroesophageal cancers are enriched in KRAS wild-typeWT amplified tumors. (n=3464) were selected from the AACR Genie MSK and DFCI cohort (version v16.0-public). Only patients with any alterations above listed genes shown (1498 unaltered not shown). Co-alterations ranked by frequency. samples defined a GISTIC score of 2 according to GENIE as exact copy number thresholds available cohort.</p>
<p>Supplementary Figure 5. Anti-proliferative activity of RMC-7977 across different KRAS altered cell lines. (Left) (2) mutant or wild-type amplified Cell lines are sorted by median sensitivity alleles. Note: AUC values relative measures drug and therefore suitable to compare for a single compound but do not allow comparison compounds. (Right) Comparison with dependency on either KRAS, HRAS NRAS. Chronos score (gene effect score) less than -1 were considered dependent. Sensitivity...
<p>Supplementary Figure 3. Relationship between KRAS wild-type amplification and oncogenic activity in cell lines. RAS activation signatures (1,3) MSigDB, KrasLA, KRASG13D134, HRAS, MPAS, ras84 addiction amplified lines (relative copy number >7) compared to with a lower relative (2-7) mutated without amplification. Enrichment scores were estimated using single sample enrichment (ssGSEA). A one-sided Wilcox-test was used test for significance of 2-7 or >7. Adjusted P-values...
<p>Supplementary Figure 10. BI-2493 treatment in animal models is tolerated. % bodyweight change xenograft treated with control vehicle or BI-2493. Data represent the mean +/- SEM of mice grafted with: (A) DMS 53 cells (N=7); (B) MKN1 (N=7). One group had to be sacrificed earlier (d11) due loss. (C) ES11082 PDX model (N=8). Two animals and three (d18, d18, d15, d12, d7, respectively). (D) GA6871 2 (d7 d16, d30, respectively) loss.</p>