775 research outputs found

    Wochenendspiegel / Vogtland

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    Forschungsbericht / Hochschule Mittweida

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    Wochenendspiegel Erzgebirge / Annaberg

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    Wochenendspiegel Erzgebirge / Stollberg

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    Wochenendspiegel Erzgebirge / Annaberg

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    Wochenendspiegel / Vogtland

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    Exploiting molecular vulnerabilities in genetically defined lung cancer models

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    Lung cancer is the leading cause of cancer-related death worldwide, with approximately 1.8 million deaths in 2020. Based on histology, lung cancer is divided into non-small cell lung cancer (NSCLC) (85 %) and small cell lung cancer (SCLC) (15 %). The most common types of NSCLC are lung squamous cell carcinoma (LUSC), large-cell carcinoma (LCC), and lung adenocarcinoma (LUAD). LUAD, the largest subgroup of NSCLC, is characterized by genomic alterations in oncogenic driver genes such as KRAS or EGFR. Mutations in the kinase domain of EGFR result in aberrant signaling activation and subsequent cancer development. Tyrosine kinase inhibitors (TKIs) selectively target and inhibit mutant kinases, thereby killing oncogene-addicted cancer cells. The introduction of TKIs into clinical practice shifted NSCLC treatment from cytotoxic chemotherapy towards precision medicine, improving both survival and the quality of life during therapy. Patients with canonical EGFR mutations like the point-mutation L858R or exon 19 deletions mutations, which account for the majority of EGFR mutations, respond well to EGFR targeted TKIs. However, rare mutations like insertions in exon 20 insertions still represent challenging drug targets. C-helix–4-loop insertion mutations in exon 20 push the C-helix into the active, inward position without altering the binding site for TKIs. This leaves the binding site for TKIs in kinases with exon 20ins mutations highly similar to wild type (WT) EGFR. Thus, the challenge in the development of exon 20 inhibitors is the design of wild type sparing small molecules. Here, we analyzed a novel small molecule EGFR inhibitor (LDC0496) targeting an emerging cleft in exon 20-mutated EGFR to achieve selectivity over the wild type. In contrast to classical EGFR TKIs, LDC0496 reduces the cellular viability of EGFR exon 20 mutated cells but spares wild type EGFR. Targeted therapy inevitably results in the development of on- or off-target resistance. Drug induced resistance mutations require the constant development of novel drugs targeting the diverse landscape of resistance mechanisms. We detected BRAF mutations in EGFR-driven lung cancer patients as a resistance mechanism to EGFR inhibitors. Notably, we also detected co-occurrence of EGFR and BRAF mutations before treatment start. Combination treatment of EGFR and mitogen-activated protein kinase kinase (MEK) inhibition displayed activity in BRAF- and EGFR-mutated xenograft studies, therefore providing a treatment strategy to overcome BRAF mutation as a resistance mechanism. Compared to NSCLC, SCLC lacks druggable targets and the initial chemosensitive state rapidly turns into a chemoresistance state. SCLC is genetically defined by a biallelic loss of tumor suppressors RB1 and TP53 and alterations of MYC family members. The transcription factor MYC is a challenging target that cannot be directly targeted. Therefore, alternative strategies are needed, for example targeting its co-factors, such as the MYC-interacting zinc finger protein 1 (MIZ1). To study the complex interplay of Myc–Miz1 in SCLC, we developed a novel mouse model with a truncated Miz1, which is unable to stably bind chromatin (RPMM: Rb1fl/flTrp53fl/flMycLSL/LSLMIZ1∆POZfl/fl). Compared to Miz1 wild type the characterization of the novel mouse model revealed tumor-onset, localization, size and immune infiltration to be unaffected by the ablation of the Miz1-POZ domain, but mice with Miz1-∆POZ live longer, exhibit an increased number of apoptotic cells and are more sensitive towards chemotherapy. We found that truncated Miz1 alter SCLC tumorigenesis towards a less aggressive phenotype and prolongs the chemosensitive state. Our study highlights alternative strategies to define novel vulnerabilities and options to overcome chemoresistance
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