A5025317705- Synthesis and Biological Evaluation
- Synthesis and biological activity
- Click Chemistry and Applications
- Bioactive Compounds and Antitumor Agents
- Cancer Immunotherapy and Biomarkers
- Peptidase Inhibition and Analysis
- Ferroptosis and cancer prognosis
- Immune cells in cancer
- Immunotherapy and Immune Responses
- Chemical Synthesis and Analysis
- Adenosine and Purinergic Signaling
- Mathematical Biology Tumor Growth
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Metabolism, Diabetes, and Cancer
- Cell Adhesion Molecules Research
- PI3K/AKT/mTOR signaling in cancer
- Inflammatory mediators and NSAID effects
- Lung Cancer Treatments and Mutations
- Galectins and Cancer Biology
- Ubiquitin and proteasome pathways
- Protein Tyrosine Phosphatases
- HER2/EGFR in Cancer Research
- Phagocytosis and Immune Regulation
The Francis Crick Institute
2021-2024
Heidelberg University
2019
DKFZ-ZMBH Alliance
2019
German Cancer Research Center
2019
Abstract In this study, the impact of apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell (NSCLC) mouse models constrained tumorigenesis, while tumors treated with EGFR-targeted therapy associated treatment resistance. Analyses human NSCLC showed upregulation and revealed therapy-induced activation nuclear kappa (NF-κB) as an...
Abstract Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic drives evasion is needed identify approaches that could sensitize KRAS-mutant lung cancer immunotherapy. In vivo CRISPR–Cas9 screening in an immunogenic murine model identified promotes evasion, most notably via upregulation immunosuppressive COX2 cells. potently induced both mouse...
Abstract Mutant selective drugs targeting the inactive, GDP-bound form of KRAS G12C have been approved for use in lung cancer, but resistance develops rapidly. Here we an inhibitor, (RMC-4998) that targets RAS its active, GTP-bound form, to treat mutant cancer various immune competent mouse models. pathway reactivation after RMC-4998 treatment could be delayed using combined with a SHP2 which not only impacts tumour cell signalling also remodels microenvironment less immunosuppressive. In...
In the process of epithelial-mesenchymal transition (EMT), epithelial cancer cells transdifferentiate into mesenchymal-like with high motility and aggressiveness, resulting in spread tumor cells. Immune inflammation microenvironment are driving factors EMT, but few studies have explored core targets interaction between EMT immune We analyzed thousands cases gastric tissue specimens TCGA, CPTAC, GTEx analyzing QPCR IHC data 56 patients SYSU Gastric Cancer Research Center. It was known that...
Abstract The recent approval of KRASG12C mutant-specific inhibitors has transformed the clinical practice lung cancer patients harboring mutations. However, data show that resistance develops rapidly after initial responses, suggesting combination therapies will be needed. Ideally, these combinations should not only overcome adaptive or acquired but also maintain even enhance positive immunomodulatory effects (G12Ci) have in tumor microenvironment (TME). Most G12Ci being tested trials target...
<div>Abstract<p>Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic drives evasion is needed identify approaches that could sensitize KRAS-mutant lung cancer immunotherapy. <i>In vivo</i> CRISPR–Cas9 screening in an immunogenic murine model identified promotes evasion, most notably via upregulation immunosuppressive...
<p><i>In vivo</i> CRISPR–Cas9 screen identifies regulators of antitumor immunity. <b>A,</b> Schematic pooled screen. <b>B,</b> sgRNAs targeting genes depleted <i>in vitro</i> compared with nontarget controls. The CRISPR score is defined as the average log<sub>2</sub>-fold change in abundance sgRNA reads at day 28 (<i>in vitro</i>) vs. 0 for each gene. <b>C,</b> <i>Cflar</i> and...
<p>Tumor-intrinsic COX2 suppresses antitumor immunity. <b>A,</b> Kaplan–Meier survival of mice treated with 200 μg anti-NK1.1 and/or anti-CD8 or corresponding isotype control (<i>n</i> = 5–7 per group) after orthotopic transplantation <i>Ptgs2</i><sup>−<i>/</i>−</sup> cells. Treatment was initiated 3 days before and administered once weekly until endpoint. Analysis curves carried out using the log-rank (Mantel–Cox) test....
<p>In vivo screen identifies mediators of immune resistance and sensitivity</p>
<p>In vivo screen identifies mediators of immune resistance and sensitivity</p>
<p>Supplementary Figure 5. Flow cytometry gating strategies</p>
<p>Supplementary Figure 3. Oncogenic KRAS inhibits tumor-intrinsic IFN responses via Myc</p>
<p>Oncogenic KRAS drives immunosuppressive COX2 expression in lung adenocarcinoma. <b>A,</b> Immunoblot for (left) and ELISA analysis PGE2 concentration (right) KPAR cells treated with 10 nmol/L trametinib (MEKi) 24 hours or 48 hours. <b>B</b> <b>C,</b> (<b>B</b>) (<b>C</b>) KRAS<sup>G12C</sup> mouse cancer cell lines 100 MRTX849 <b>D,</b> mRNA 3LL ΔNRAS KPAR<sup>G12C</sup> orthotopic tumors...
<p>Tumor-intrinsic COX2 suppresses antitumor immunity. <b>A,</b> Kaplan–Meier survival of mice treated with 200 μg anti-NK1.1 and/or anti-CD8 or corresponding isotype control (<i>n</i> = 5–7 per group) after orthotopic transplantation <i>Ptgs2</i><sup>−<i>/</i>−</sup> cells. Treatment was initiated 3 days before and administered once weekly until endpoint. Analysis curves carried out using the log-rank (Mantel–Cox) test....
<p>Dual inhibition of EP2 and EP4 synergizes with ICB. <b>A–C,</b> M1/M2 macrophage ratio (<b>A</b>), percentage Arg1<sup>+</sup> CD11b<sup>+</sup> TAMs (<b>B</b>), CD69<sup>+</sup> CD8<sup>+</sup> T cells (<b>C</b>) in KPAR tumors treated twice daily for 7 days 100 mg/kg TPST-1495. <b>D,</b> Kaplan–Meier survival mice intraperitoneally 200 μg anti-PD1 and/or oral gavage...
<p>Supplementary Figure 9. Oncogenic KRAS drives tumor-intrinsic expression of COX-2 in LUAD</p>
<p>Supplementary Figure 2. KRAS-driven inhibition of tumor-intrinsic IFN signaling promotes immune evasion</p>
<p>Supplementary Figure 9. Oncogenic KRAS drives tumor-intrinsic expression of COX-2 in LUAD</p>
<p>Oncogenic KRAS drives immunosuppressive COX2 expression in lung adenocarcinoma. <b>A,</b> Immunoblot for (left) and ELISA analysis PGE2 concentration (right) KPAR cells treated with 10 nmol/L trametinib (MEKi) 24 hours or 48 hours. <b>B</b> <b>C,</b> (<b>B</b>) (<b>C</b>) KRAS<sup>G12C</sup> mouse cancer cell lines 100 MRTX849 <b>D,</b> mRNA 3LL ΔNRAS KPAR<sup>G12C</sup> orthotopic tumors...
<p>Supplementary Figure 7. Genetic loss of COX-2 signaling synergizes with ICB</p>
<p>Supplementary Figure 5. Flow cytometry gating strategies</p>