Biology subjects

Bayer, F. P.

Publications and source records attributed to Bayer, F. P..

4 recordsLinked to original sources

bioRxiv2025

Illuminating oncogenic KRAS signaling by multi-dimensional chemical proteomics

Mutated KRAS is among the most frequent activating genetic alterations in cancer and drug discovery efforts have led to inhibitors that block its activity. To better understand oncogenic KRAS signaling and the cytostatic effects of drugs, we performed comprehensive dose-dependent proteome-wide target deconvolution, pathway engagement and protein expression characterization of KRAS, MEK, ERK, SHP2 and SOS1 inhibitors in pancreatic (KRAS G12C, G12D) and lung cancer (KRAS G12C) cells. Analysis of the resulting 687,954 dose-response curves available online revealed both common and cell line-specific signaling networks dominated by oncogenic KRAS activity. Time-dose experiments separated early KRAS-MEK-ERK from CDK-mediated signaling that cause cells to exit from the cell cycle. This transition to a quiescent state occurred without substantial proteome re-modelling but extensive changes of protein phosphorylation and ubiquitylation. The collective data highlights the complexity of KRAS signaling in cancer and places a large number of new proteins into this functional context.

cell biology↗

bioRxiv2024

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response

The DNA-damaging agent gemcitabine (GEM) is a first-line treatment for pancreatic cancer but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs including kinase inhibitors but the experimental evidence for such rational is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 140 clinical kinase inhibitors and observed strong synergy for the ATR inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway including phosphorylated pS468 of CHEK1 as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

cancer biology↗

bioRxiv2023

PTMNavigator: Interactive Visualization of Differentially Regulated Post-Translational Modifications in Cellular Signaling Pathways

Post-translational modifications (PTMs) play pivotal roles in regulating cellular signaling, fine-tuning protein function, and orchestrating complex biological processes. Despite their importance, the lack of comprehensive tools for studying PTMs from a pathway-centric perspective has limited our ability to understand how PTMs modulate cellular pathways on a molecular level. Here, we present PTMNavigator, a tool integrated into the ProteomicsDB platform, which offers an interactive interface for researchers to overlay experimental PTM data with pathway diagrams. PTMNavigator provides [~]3000 canonical pathways from manually curated databases and further enables users to modify and create custom diagrams, tailored to their data. Additionally, PTMNavigator automatically runs multiple kinase and pathway enrichment algorithms whose results are directly integrated into the visualization. This offers a comprehensive view of the intricate relationship between PTMs and signaling pathways. To demonstrate the utility of PTMNavigator, we applied it to two phosphoproteomics perturbation datasets. First, PTMNavigator enhanced pathway enrichment analysis by showing how the regulated peptides and proteins are distributed in the pathways with high enrichment scores. Second, it visualized how drug treatments result in a discernable flow of PTM-driven signaling within pathways. Third, PTMNavigator aided in proposing extensions to an existing pathway by suggesting putative new links between both PTMs and pathway components. By enhancing our understanding of cellular signaling dynamics and facilitating the discovery of novel PTM-pathway interactions, PTMNavigator advances our knowledge of PTM biology and its implications in health and disease.

systems biology↗

bioRxiv2023

CurveCurator: A recalibrated F-statistic to assess, classify, and explore significance of dose-response curves

Dose-response curves are key metrics in pharmacology and biology to assess phenotypic or molecular actions of bioactive compounds in a quantitative fashion. Yet, it is often unclear whether or not a response significantly differs from a curve without regulation, particularly in high-throughput applications or unstable assays. Treating potency and effect size estimates from random and true curves with the same level of confidence can lead to incorrect hypotheses and issues in training machine learning models. Here, we present CurveCurator, an open-source software and interactive dashboard that provides reliable dose-response characteristics by computing p-values and false discovery rates based on a recalibrated F-statistic and a novel thresholding procedure. Application of CurveCurator to large-scale data sets demonstrates its scalable utility across several application areas.

bioinformatics↗