A5015413269- Pancreatic and Hepatic Oncology Research
- Advanced Breast Cancer Therapies
- Colorectal Cancer Treatments and Studies
- Cancer, Hypoxia, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Growth Hormone and Insulin-like Growth Factors
- Neuroendocrine Tumor Research Advances
- Protein Kinase Regulation and GTPase Signaling
- Autophagy in Disease and Therapy
- Melanoma and MAPK Pathways
- Caveolin-1 and cellular processes
- Endoplasmic Reticulum Stress and Disease
- Cancer Mechanisms and Therapy
- Pancreatic function and diabetes
- Cancer Genomics and Diagnostics
- Protein Degradation and Inhibitors
- Cellular transport and secretion
- Cell Adhesion Molecules Research
- Effects of Radiation Exposure
- Histone Deacetylase Inhibitors Research
- DNA Repair Mechanisms
- Ubiquitin and proteasome pathways
- Cancer Treatment and Pharmacology
- Parathyroid Disorders and Treatments
- Advanced biosensing and bioanalysis techniques
Charité - Universitätsmedizin Berlin
2022-2025
German Cancer Research Center
2022-2025
Heidelberg University
2022-2025
Humboldt-Universität zu Berlin
2024
Freie Universität Berlin
2024
University of North Carolina at Chapel Hill
2017-2024
Deutschen Konsortium für Translationale Krebsforschung
2024
Institute of Molecular Biology
2022
Berlin Institute of Health at Charité - Universitätsmedizin Berlin
2022
UNC Lineberger Comprehensive Cancer Center
2020
Abstract Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether functionally distinct from more KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). found KRASG12D/V but not drives...
Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation KRAS in promoting the development and malignant growth pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration p16INK4A with inhibitors CDK4 CDK6 (CDK4/6) has shown limited clinical efficacy PDAC. Here, we found concurrent treatment both CDK4/6 inhibitor (CDK4/6i) an ERK-MAPK (ERKi) synergistically suppresses PDAC cell lines organoids by cooperatively...
Abstract The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that small-molecule Deltarasin binds to pocket PDEδ, and impairs Ras enrichment at membrane, thereby affecting proliferation KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, now identified pyrazolopyridazinones as a novel, unrelated chemotype with high affinity, displacing proteins in cells. Our...
We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF ERK (ERKi), is highly synergistic at low doses cell line, organoid, rat models PDAC, whereas each alone only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA)...
The localization and signaling of S-palmitoylated peripheral membrane proteins is sustained by an acylation cycle in which acyl protein thioesterases (APTs) depalmitoylate mislocalized palmitoylated on endomembranes. However, the APTs are themselves reversibly S-palmitoylated, localizes thioesterase activity to site antagonistc palmitoylation Golgi. Here, we resolve this conundrum showing that labile due autodepalmitoylation, creating two interconverting pools: APT Golgi depalmitoylated...
Abstract The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development improved therapies. As KRAS mutations are found in 95% PDAC and critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. macrometabolic process autophagy is upregulated KRAS-mutant PDAC, growth reliant on autophagy. However, inhibition as monotherapy using lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy....
Precise quantification of endogenous protein–protein interactions across live cells would be a major boon to biology. Such precise measurement is theoretically possible with fluorescence lifetime imaging microscopy (FLIM) but requires first properly addressing multiple biological, instrumental, statistical, and photophysical challenges. We present detailed investigation the last three FLIM-specific Using an efficient, highly accurate analysis code for time-domain FLIM data that accounts all...
Highlights•p130Cas and βIII-tubulin support PDAC growth by enhancing MYC expression•p130Cas transcriptionally regulates through SRC-p130Cas-DOCK1-RAC1-β-catenin•Microtubules post-translationally regulate stability calpains•Triple targeting of ERK/p130Cas/tubulin with ERKi KX2-391 inhibits growthSummaryTo identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen determine that suppression BCAR1 sensitizes cancer cells to...
Abstract The stress-associated chaperone system is an actionable target in cancer therapies. It ubiquitously upregulated tissues and enables tumorigenicity by stabilizing oncoproteins. Most inhibitors the key component, heat-shock protein 90 (HSP90). Although HSP90 are highly tumor-selective, they fail clinical trials. These failures partly due to interference with a negative regulatory feedback loop response (HSR): inhibition, there compensatory synthesis of stress-inducible chaperones,...
Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile the KRAS-regulated kinase network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). knocked down expression panel six cell lines and then applied multiplexed inhibitor bead/MS monitor changes activity and/or expression. hypothesized that depletion would result downregulation kinases required for KRAS-mediated...
Oncogenic mutations in the KRAS gene are well-established drivers of cancer. While recently developed KRASG12C inhibitors offer a targeted therapy and have shown success clinic, represents only 11% all mutations. Current therapeutic approaches for other both indirect nonmutant-selective, largely focusing on inhibition downstream effectors such as MAP kinases. Inhibition signaling results system-wide down-modulation respective targets, raising concerns about systemic cell toxicity. Here, we...
ABSTRACT The stress-associated molecular chaperone system is an actionable target in cancer therapies. It ubiquitously upregulated tissues and enables tumorigenicity by stabilizing hundreds of oncoproteins disturbing the stoichiometry protein complexes. Most inhibitors key component heat-shock 90 (HSP90). However, although classical HSP90 are highly tumor-selective, they fail phase 3 clinical oncology trials. These failures at least partly due to interference with a negative feedback loop...
<title>Abstract</title> Background Colorectal cancer is the third most common tumour entity in world and up to 50% of patients develop liver metastases (CRLM) within five years. To improve personalize therapeutic strategies, new diagnostic tools are urgently needed. For instance, biomechanical properties measured by magnetic resonance elastography (MRE) could be implemented as such a tool. We postulate that <italic>ex vivo</italic> MRE combined with histological radiological evaluation CRLM...
Abstract Background Colorectal cancer is the third most common tumour entity in world and up to 50% of patients develop liver metastases (CRLM) within five years. To improve personalize therapeutic strategies, new diagnostic tools are urgently needed. For instance, biomechanical properties measured by magnetic resonance elastography (MRE) could be implemented as such a tool. We postulate that ex vivo MRE combined with histological radiological evaluation CRLM provide biomechanics-based...
Secondary resistance limits the clinical effectiveness of mutation-specific RAS inhibitors in colorectal cancer. It is unknown whether broad-spectrum meet similar limitations. Here, we identify and categorize mechanisms to active-state inhibitor RMC-7977 cancer cell lines. We found that KRAS-mutant lines are universally sensitive RMC-7977, inhibiting RAS-RAF-MEK-ERK axis, halting proliferation some cases inducing apoptosis. To monitor KRAS downstream effector pathway activity, developed a...