Johannes M. Heuckmann
A5052066844- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
- Lung Cancer Research Studies
- Colorectal Cancer Treatments and Studies
- Cancer Genomics and Diagnostics
- Fibroblast Growth Factor Research
- Computational Drug Discovery Methods
- HER2/EGFR in Cancer Research
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Neuroendocrine Tumor Research Advances
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Cancer Mechanisms and Therapy
- Cancer-related gene regulation
- PI3K/AKT/mTOR signaling in cancer
- Genetic factors in colorectal cancer
- Metastasis and carcinoma case studies
- Synthesis and biological activity
- Eosinophilic Disorders and Syndromes
- Salivary Gland Tumors Diagnosis and Treatment
- Kruppel-like factors research
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Sarcoma Diagnosis and Treatment
- Renal cell carcinoma treatment
Max Planck Society
2009-2023
Max Planck Institute for Metabolism Research
2009-2023
Max Planck Institute for the Study of Societies
2010-2023
Disco (Germany)
2023
University of Cologne
2009-2015
Assistance Publique Hôpitaux de Marseille
2015
Université Toulouse III - Paul Sabatier
2015
Aix-Marseille Université
2015
Integrated Oncology (United States)
2010-2014
Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
2014
FGFR1 amplification provides a therapeutic target for squamous cell lung cancer, which is resistant to other targeted cancer drugs.
While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell cancer. Sanger sequencing of tyrosine kinome identified mutations in DDR2 kinase gene 3.8% cancers and lines. Squamous cancer lines harboring were selectively killed by knock-down RNAi or treatment multi-targeted inhibitor dasatinib. Tumors established from a mutant line sensitive to dasatinib xenograft models. Expression...
Approximately 1% of lung adenocarcinomas are driven by oncogenic ROS1 rearrangement. Crizotinib is a potent inhibitor both and ALK kinase domains.In the absence prospective clinical trial in Europe, we conducted retrospective study centers that tested for Eligible patients had stage IV adenocarcinoma, rearrangement according to fluorescent situ hybridization, received crizotinib therapy through an individual off-label use. Best response was assessed locally using RECIST (version 1.1). All...
A systematic look at a childhood tumor Neuroblastomas—the most common type in infants—develop from fetal nerve cells, and their clinical course is highly variable. Some neuroblastomas are fatal despite treatment, whereas others respond well to treatment some undergo spontaneous regression without treatment. Ackermann et al. sequenced more than 400 pretreatment identified molecular features that characterize the three distinct outcomes. Low-risk tumors lack telomere maintenance mechanisms,...
ALK rearrangement-positive lung cancers can be effectively treated with inhibitors. However, the magnitude and duration of response is heterogeneous. In addition, acquired resistance limits efficacy inhibitors, most upfront mechanisms being unknown.By making use Ba/F3 cell line model, we analyzed cytotoxic kinase inhibitors as a function different EML4-ALK fusion variants v1, v2, v3a, v3b well three artificially designed deletion constructs genes KIF5b-ALK NPM1-ALK. intracellular...
We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas never smokers. By screening 102 negative for known oncogenic alterations, we found four additional fusion-positive tumors, all which were the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression EGF-like domain NRG1 III-β3, thereby providing ligand ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 was high in index case, phospho-ERBB3...
To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy either AZD9291 or rociletinib (CO-1686).
In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of mutant oncoprotein. Therapeutic inhibition these oncoproteins can massive apoptosis tumor cells, leading to sometimes dramatic regressions in patients. The PI3K and MAPK signaling pathways are central regulators oncogenic transformation maintenance. We hypothesized that upstream engages either one preferentially "downstream" dependency. Therefore, we analyzed whether downstream pathway...
Abstract Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in pathogenesis multiple human cancers, where ALK represents a rational therapeutic target these settings. In this study, we report identification and biological characterization X-376 X-396, two potent highly specific small molecule tyrosine inhibitors (TKIs). Ambit kinome screens, cell growth inhibition studies, surrogate assays, X-396 were more but less MET compared to PF-02341066 (PF-1066), an ALK/MET...
Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival patients with EGFR-mutated lung cancers. Second-generation EGFR introduced overcome acquired resistance by T790M mutation have thus far shown limited clinical activity in T790M-mutant tumors. In this study, we systematically analyzed determinants and selectivity second-generation inhibitors. A focused library irreversible as well structurally corresponding...
Abstract Purpose: EML4–ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, better understanding mechanisms will help to enhance tumor control in EML4–ALK-positive tumors. Experimental Design: By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing...
Small cell lung cancer (SCLC) accounts for about 15% of all cancers. The prognosis SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework development specific SCLC-targeted drugs we conducted combined genomic pharmacological vulnerability screen lines. We show that lines capture the landscape primary tumors provide genetic predictors activity clinically relevant inhibitors by screening 267 compounds across 44 these Aurora...
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as dysregulation these elementary transducers extracellular signals, like epidermal growth factor receptor (EGFR), contributes to onset cancer, such non-small cell lung (NSCLC). Strong efforts were directed development irreversible inhibitors and led compound CO-1686, which takes advantage increased residence time at EGFR by alkylating Cys797 thereby preventing toxic effects. Here, we present a structure-based...
The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it currently unknown which of 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, contrast with other recurrent amplifications, region included multiple centers amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands vitro and vivo. Furthermore, ectopic...
Purpose: We sought to investigate the clinical response MET inhibition in patients diagnosed with structural alterations and characterize their functional relevance cellular models.Experimental Design: Patients were selected for treatment crizotinib upon results of hybrid capture-based next-generation sequencing. To confirm observations, we analyzed models that express these kinase alterations.Results: Three individual identified harbor within receptor. Two showed genomic rearrangements,...
Article Tools UNDERSTANDING THE PATHWAY OPTIONS & TOOLS Export Citation Track Add To Favorites Rights Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2012.43.1825 Journal of Clinical Oncology - published online before print August 20, 2012 PMID: 22915655 Epidermal Growth Factor Receptor (EGFR) Signaling and Covalent EGFR Inhibition in Lung Cancer Johannes M. HeuckmannxJohannes HeuckmannSearch for by this author , Daniel RauhxDaniel RauhSearch Roman K....
An examination of the activity profiles RET inhibitors suggests potential treatment for -rearranged cancers.
Detection of somatic genomic alterations in the plasma patients with cancer ("liquid biopsy") are increasingly being used clinic. However, concordance identified liquid biopsies those detected specimens is not routinely determined.We sought to systematically compare found by a massively parallel sequencing biopsy assay covering 39 genes (NEOliquid [NEO New Oncology GmbH, Köln, Germany]) through routine diagnostic testing certified central pathology laboratory cohort nonsquamous NSCLC....
Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) ( https://github.com/ruping/TRUP ), a computational approach that combines split-read and read-pair analysis de novo assembly for the identification chimeric in specimens....
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...
Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor 1 (FGFR1) being one of most prominent targets this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% such tumors respond single-agent FGFR inhibition and several exhibited insufficient tumor shrinkage, compatible with existence drug-resistant cells.Experimental Design: To...