A5063585604- Computational Drug Discovery Methods
- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Protein Degradation and Inhibitors
- Colorectal Cancer Treatments and Studies
- Fibroblast Growth Factor Research
- Advanced Breast Cancer Therapies
- Synthesis and biological activity
- Multiple Myeloma Research and Treatments
- Bioinformatics and Genomic Networks
- PARP inhibition in cancer therapy
- Cancer Immunotherapy and Biomarkers
- Cancer Mechanisms and Therapy
- Cytokine Signaling Pathways and Interactions
- Kruppel-like factors research
- PI3K/AKT/mTOR signaling in cancer
- Genetic factors in colorectal cancer
- Molecular Biology Techniques and Applications
- Genetics, Bioinformatics, and Biomedical Research
- Radiomics and Machine Learning in Medical Imaging
- Cancer therapeutics and mechanisms
- Cancer Cells and Metastasis
- Eosinophilic Disorders and Syndromes
- Single-cell and spatial transcriptomics
AstraZeneca (United States)
2013-2024
Tempus Labs (United States)
2020-2024
AstraZeneca (Brazil)
2017-2023
Bioscience Research
2023
AstraZeneca (Netherlands)
2020
AstraZeneca (United Kingdom)
2003-2015
East Cheshire NHS Trust
2015
Fred Hutch Cancer Center
2013
Sorbonne Paris Cité
2013
Koo Foundation Sun Yat-Sen Cancer Center
2013
Accurate variant calling in next generation sequencing (NGS) is critical to understand cancer genomes better. Here we present VarDict, a novel and versatile caller for both DNA- RNA-sequencing data. VarDict simultaneously calls SNV, MNV, InDels, complex structural variants, expanding the detected genetic driver landscape of tumors. It performs local realignments on fly more accurate allele frequency estimation. performance scales linearly depth, enabling ultra-deep used explore tumor...
Abstract Resistance to targeted EGFR inhibitors is likely develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms these agents essential direct development future therapies. We describe the detection heterogeneous within populations cells (PC9 and/or NCI-H1975) with current and newly developed tyrosine kinase inhibitors, including AZD9291. report NRAS mutations, a novel E63K mutation, gain copy number WT KRAS cell resistant gefitinib, afatinib,...
Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (MEK)-1/2. The range antitumor activity seen preclinically and in patients highlights the importance identifying determinants response to this drug. In large tumor cell panels diverse lineage, we show that MEK does not have an absolute correlation with mutational or phospho-protein markers BRAF/MEK, RAS, phosphoinositide 3-kinase (PI3K) activity....
Resistance to cancer therapeutics targeting the second kinase in a three-kinase cascade involves amplification of upstream kinase, not inhibited kinase.
The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting bromodomains by small molecule inhibitors has proven be an effective means disrupt aberrant programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, orally available BET/BRD4 inhibitor possessing bivalent binding mode. Unlike previously described monovalent...
Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study evolution, mechanisms of drug response and resistance, tailoring chemotherapeutic approaches for individual patients. The lack robust standards reporting on PDX has hampered the ability researchers find relevant associated data. Here we present minimal information standard (PDX-MI) generation, quality assurance, use models. PDX-MI defines describing clinical attributes a...
There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification cancers with a significant drive is critical to understand potential for these molecules. However, it challenging measure tumor levels at scale, thus novel, clinically tractable biomarkers needed.We generated gene expression signature signaling using regulatory networks derived from literature validated this patients. We applied large cohorts disease...
Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable reproducible methods profile these models. We describe robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate genetic transcriptomic concordance this approach...
Resistance to EGFR inhibitors (EGFRi) presents a major obstacle in treating non-small cell lung cancer (NSCLC). One of the most exciting new ways find potential resistance markers involves running functional genetic screens, such as CRISPR, followed by manual triage significantly enriched genes. This process identify 'high value' hits resulting from CRISPR screen curation that requires specialized knowledge and can take even experts several months comprehensively complete. To key drivers...
Abstract The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis mixed intra-patient tumor remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations EGFR and TP53 , are more likely have tyrosine kinase inhibition (TKI), compared those mutation alone. combined presence whole genome doubling (WGD) leads increased instability...
Abstract BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X L expression biases pool towards MCL1. Consequently, or synthetic lethal with MCL1 inhibitor AZD5991, driving profound tumour cell death requires BAK/BAX, inhibiting growth vivo. Combination...
With the introduction of DNA-damaging therapies into standard care cancer treatment, there is a growing need for predictive diagnostics assessing homologous recombination deficiency (HRD) status across tumor types. Following strong clinical evidence utility DNA-sequencing-based HRD testing in ovarian cancer, and breast we present analytical validation Tempus HRD-DNA test. We further developed, validated, explored HRD-RNA model, which uses gene expression data from 16,750 RNA-seq samples to...
Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority patients experience long-term disease control. Using large, clinically annotated cohort with metastatic hormone receptor-positive (HR+) cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) be associated lack Human cancer models reveal that p53 does not alter activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence...
Abstract Drug combinations can expand therapeutic options and address cancer’s resistance. However, the combinatorial space is enormous precluding its systematic exploration. Therefore, synergy prediction strategies are essential. We here present an approach to prioritise drug in high-throughput screens stratify synergistic responses. At core of our observation that likelihood increases when targeting proteins with either strong functional similarity or dissimilarity. estimate applying a...
Abstract Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF V600E or KRAS G13D reinstate ERK1/2 signalling. Here we show that and MEKi are reversible following drug withdrawal. Cells with addicted maintain a precise level signalling is optimal for cell proliferation survival, tumour growth in vivo. Robust activation withdrawal drives p57 KIP2 -dependent G1 cycle arrest senescence expression NOXA death, selecting against those cells amplified . required loss...
Abstract Immuno-oncology (IO) therapies have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC). However, patient responses to IO are variable and influenced by a heterogeneous combination health, immune, tumor factors. There is pressing need discover distinct NSCLC subgroups that influence response. We developed dee p pa tient graph convolutional n etwork, we call “DeePaN”, complexity across data modalities impacting benefit. DeePaN employs high-dimensional derived...
Abstract Background DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it important understand landscape across different solid types. Methods Germline somatic BRCA mutations in breast ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed validate TCGA results determine...
Combinations of therapies are being actively pursued to expand therapeutic options and deal with cancer's pervasive resistance treatment. Research efforts discover effective combination treatments have focused on drugs targeting intracellular processes the cancer cells in particular small molecules that target aberrant kinases. Accordingly, most computational methods used study, predict, develop drug combinations concentrate these modes action signaling within cell. This focus cell overlooks...
Abstract Personalized therapy is a major goal of modern oncology, as patient responses vary greatly even within histologically defined cancer subtype. This especially true in acute myeloid leukemia (AML), which exhibits striking heterogeneity molecular segmentation. When calibrated to cell-specific data, executable network models can reveal subtle differences signaling that help explain drug response. Furthermore, they suggest combinations increase efficacy and combat acquired resistance....
: PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration the therapeutic potential inhibition been limited targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions mono(ADP-ribose) PARP6, remain largely uncharacterized. Here, we report novel strategy PARP6 using first reported inhibitors. By screening collection...
The image in the top panel of Fig. 1C was erroneously reversed during processing manuscript.
Abstract Purpose: KRAS wild-type status is an imperfect predictor of sensitivity to anti-EGF receptor (EGFR) monoclonal antibodies in colorectal cancer, motivating efforts identify novel molecular aberrations driving RAS. This study aimed build a quantitative readout RAS pathway activity (i) uncover surrogates specific (ii) improve the prediction cetuximab response patients, and (iii) suggest new treatment strategies. Experimental Design: A model was trained large cancer dataset validated...