A5036838488- Lung Cancer Treatments and Mutations
- RNA modifications and cancer
- HER2/EGFR in Cancer Research
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Cancer Genomics and Diagnostics
- Cancer therapeutics and mechanisms
- Lung Cancer Research Studies
- RNA Research and Splicing
- Evolution and Genetic Dynamics
- Heat shock proteins research
- Liver physiology and pathology
- Neuroblastoma Research and Treatments
- Bioinformatics and Genomic Networks
- PI3K/AKT/mTOR signaling in cancer
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Ferroptosis and cancer prognosis
- Quinazolinone synthesis and applications
- Crystallization and Solubility Studies
- Antibiotic Resistance in Bacteria
- Cancer, Hypoxia, and Metabolism
- Antimicrobial agents and applications
- Phenothiazines and Benzothiazines Synthesis and Activities
- X-ray Diffraction in Crystallography
University Hospital Cologne
2018-2024
University of Cologne
2019-2023
TU Dortmund University
2017-2020
Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate death pathways prior therapy. Yet, which these remain available SCLC is unknown. Here, through systemic analysis pathway availability SCLC, we identify non-neuroendocrine (NE) be vulnerable ferroptosis subtype-specific lipidome remodeling. While NE resistant, it acquires addiction the TRX anti-oxidant pathway. In experimental settings non-NE/NE intratumoral heterogeneity, non-NE or...
Abstract The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In subgroup these patients we identified an association between selection EGFR T790M -negative but G724S -positive subclones and osimertinib resistance. We demonstrate that limits the activity third-generation inhibitors both vitro vivo. Structural analyses computational modeling indicate mutations may induce conformation glycine-rich loop, which is...
Inhibition of the epidermal growth factor receptor represents one most promising strategies in treatment lung cancer. Acquired resistance compromises clinical efficacy EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes against third-generation inhibitors. Here we present a rational approach based on extending inhibition profile p38 MAP kinase inhibitor toward mutant inhibition. We used privileged scaffold with proven cellular potency as well vivo...
Abstract MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of -paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using unique cellular CRISPR activation model, we uncover that, contrast MYCN and MYCL, represses BCL2 transcription via interaction with MIZ1 DNMT3a. The resulting lack expression promotes sensitivity cycle control inhibition dependency on MCL1. Furthermore,...
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks drastic change the treatment non-small cell lung (NSCLC). recurrent emergence resistance to these drugs requires development novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report optimization process for hit compound has emerged from phenotypic screen resulting indazole-based compounds. These inhibitors are...
Despite the clinical efficacy of epidermal growth factor receptor (EGFR) inhibitors, a subset patients with non-small cell lung cancer displays insertion mutations in exon20 EGFR and Her2 limited treatment options. Here, we present development characterization novel covalent inhibitors LDC8201 LDC0496 based on 1H-pyrrolo[2,3-b]pyridine scaffold. They exhibited intense inhibitory potency toward as well selectivity over wild type within kinome. Complex crystal structures biochemical cellular...
We present inhibitors of drug resistant mutants EGFR including T790M and C797S. In addition, we the first X-ray crystal structures covalent in complex with C797S-mutated to gain insight into their binding mode.
Abstract Activation of MAPK signaling via BRAF mutations may limit the activity EGFR inhibitors in EGFR- mutant lung cancer patients. However, impact on selection and fitness emerging resistant clones during anti-EGFR therapy remains elusive. We tracked evolution subclonal by whole-exome sequencing performed clonal analyses individual metastases therapy. Complementary functional polyclonal -mutant cell pools showed a dose-dependent enrichment V600E loss inhibitor susceptibility. The remain...
Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe structure-guided development of series covalent and mutant-selective EGFR that effectively target T790M mutant. The pyrazolopyrimidine-based core differs structurally from aminopyrimidine-based...
Abstract The emergence of resistance to targeted therapies restrains their efficacy. development rationally guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding the trajectories that drive outgrowth resistant clones in cancer cell populations precludes design forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation screening systematically...
Mutated or amplified Her2 serves as a driver of non-small cell lung cancer mediates resistance toward the inhibition its family member epidermal growth factor receptor with small-molecule inhibitors. To date, inhibitors targeting which can be used in clinical routine are lacking, and therefore, development novel was undertaken. In this study, well-established pyrrolopyrimidine scaffold modified structural motifs identified from screening campaign more than 1600 compounds, were applied...
The influence on the resistance formation of polymers attached to antibiotics has rarely been investigated. In this study, ciprofloxacin (CIP) was conjugated poly(2-methyl-2-oxazoline)s with an ethylene diamine end group (Me-PMOx28-EDA) via two different spacers (CIP modified α,α'-dichloro- p-xylene-xCIP, CIP chloroacetyl chloride-eCIP). antibacterial activity conjugates against a number bacterial strains shows great dependence nature spacer. Me-PMOx39-EDA-eCIP, containing potentially...
Abstract NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal potentially actionable genetic in these cancers. We initially discovered CD74-NRG1 as the first fusion adenocarcinomas, many additional partners have since been identified. Here, we present transgenic mouse model provide evidence that ubiquitous expression of protein vivo leads to development at high frequency....
9030 Background: MET mutations ( MET∆ ex14 ), amplifications or translocations can activate oncogenic signaling in lung cancer and are sensitive to inhibition. Acquired resistance therapy with tyrosine kinase inhibitors (TKI) occurs inevitably. Methods: Between 2015 2018, eighteen patients MET-driven NSCLC were treated capmatinib crizotinib as single agent at our site. Rebiopsy samples from five analyzed by NGS fluoreszenz-in-situ hybridization (FISH) time of progression. Results: Of the...
Abstract A major obstacle in the efficacy of targeted therapies oncogene-driven tumors are drug-tolerant persister cells (DTPs) that build basis for outgrowth drug-resistant clones and ultimately limit patient survival. During treatment, DTPs enter a reversible senescent state to survive therapy while cell death is induced non-DTPs. Here, using RNA-Seq proteomic analyses, we identified drug-induced TGFβ2 secretion derived from different lung cancer lines. As expected, induces...
<div>Abstract<p>The emergence of resistance to targeted therapies restrains their efficacy. The development rational-ly guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding the trajectories that drive outgrowth resistant clones in cancer cell populations precludes design forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation...
<p>Suppl. Table S6, Copy number from whole exome sequencing</p>
<p>Supplementary Methods, Figures and Tables</p>
<p>Suppl. Table S7, differentially expressed genes</p>
<p>Supplementary Note covering the mathematical modelling</p>
<p>Table S5 mutations from Whole exome sequencing</p>
<p>Suppl. Table S8, candidates from CRISPR activation screen</p>