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8 results on '"Zodel, Kyra"'

2. Integrated Metabolomic and Transcriptomic Analysis of Modified Nucleosides for Biomarker Discovery in Clear Cell Renal Cell Carcinoma

Author

Mohl, Daniel A., primary, Lagies, Simon, additional, Zodel, Kyra, additional, Zumkeller, Matthias, additional, Peighambari, Asin, additional, Ganner, Athina, additional, Plattner, Dietmar A., additional, Neumann-Haefelin, Elke, additional, Adlesic, Mojca, additional, Frew, Ian J., additional, and Kammerer, Bernd, additional

Published
2023
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3. Functional Characterization of Transforming Growth Factor-β Signaling in Dasatinib Resistance and Pre-BCR + Acute Lymphoblastic Leukemia.

Author

Mostufi-Zadeh-Haghighi, Gila, Veratti, Pia, Zodel, Kyra, Greve, Gabriele, Waterhouse, Miguel, Zeiser, Robert, Cleary, Michael L., Lübbert, Michael, and Duque-Afonso, Jesús

Subjects
TRANSFORMING growth factors-beta, B cells, LYMPHOBLASTIC leukemia, CELL receptors, CELLULAR signal transduction, CELL proliferation, RESEARCH funding, DASATINIB, CELL lines, DRUG resistance in cancer cells, PHOSPHORYLATION
Abstract

Simple Summary: We focus on the characterization of the transforming growth factor-β (TGFβ) signaling pathway in B acute lymphoblastic leukemia (ALL) and in resistance to the multi-kinase inhibitor dasatinib in order to provide a better understanding of the molecular and functional mechanisms underlying leukemic transformation and the development of drug resistance. We provide evidence that TGFβ signaling is an important negative regulator of cell growth in B-cell precursor- ALL as well as in generated dasatinib-resistant ALL cells. The multi-kinase inhibitor dasatinib has been implicated to be effective in pre-B-cell receptor (pre-BCR)-positive acute lymphoblastic leukemia (ALL) expressing the E2A-PBX1 fusion oncoprotein. The TGFβ signaling pathway is involved in a wide variety of cellular processes, including embryonic development and cell homeostasis, and it can have dual roles in cancer: suppressing tumor growth at early stages and mediating tumor progression at later stages. In this study, we identified the upregulation of the TGFβ signaling pathway in our previously generated human dasatinib-resistant pre-BCR+/E2A-PBX1+ ALL cells using global transcriptomic analysis. We confirm the upregulation of the TGFβ pathway member SMAD3 at the transcriptional and translational levels in dasatinib-resistant pre-BCR+/E2A-PBX1+ ALL cells. Hence, dasatinib blocks, at least partially, TGFβ-induced SMAD3 phosphorylation in several B-cell precursor (BCP) ALL cell lines as well as in dasatinib-resistant pre-BCR+/E2A-PBX1+ ALL cells. Activation of the TGFβ signaling pathway by TGF-β1 leads to growth inhibition by cell cycle arrest at the G0/G1 stage, increase in apoptosis and transcriptional changes of SMAD-targeted genes, e.g. c-MYC downregulation, in pre-BCR+/E2A-PBX1+ ALL cells. These results provide a better understanding about the role that the TGFβ signaling pathway plays in leukemogenesis of BCP-ALL as well as in secondary drug resistance to dasatinib. [ABSTRACT FROM AUTHOR]

Published
2023
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4. ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma

Author

Seidel, Philipp, primary, Rubarth, Anne, additional, Zodel, Kyra, additional, Peighambari, Asin, additional, Neumann, Felix, additional, Federkiel, Yannick, additional, Huang, Hsin, additional, Hoefflin, Rouven, additional, Adlesic, Mojca, additional, Witt, Christian, additional, Hoffmann, David J., additional, Metzger, Patrick, additional, Lindemann, Ralph K., additional, Zenke, Frank T., additional, Schell, Christoph, additional, Boerries, Melanie, additional, von Elverfeldt, Dominik, additional, Reichardt, Wilfried, additional, Follo, Marie, additional, Albers, Joachim, additional, and Frew, Ian J., additional

Published
2022
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6. Therapeutic Effects of Inhibition of Sphingosine-1-Phosphate Signaling in HIF-2α Inhibitor-Resistant Clear Cell Renal Cell Carcinoma

Author

Hoefflin, Rouven, primary, Harlander, Sabine, additional, Abhari, Behnaz A., additional, Peighambari, Asin, additional, Adlesic, Mojca, additional, Seidel, Philipp, additional, Zodel, Kyra, additional, Haug, Stefan, additional, Göcmen, Burulca, additional, Li, Yong, additional, Lahrmann, Bernd, additional, Grabe, Niels, additional, Heide, Danijela, additional, Boerries, Melanie, additional, Köttgen, Anna, additional, Heikenwalder, Mathias, additional, and Frew, Ian J., additional

Published
2021
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7. Sensitivity and resistance of oncogenic RAS-driven tumors to dual MEK and ERK inhibition

Author

Catalano, Antonella, Adlesic, Mojca, Kaltenbacher, Thorsten, Klar, Rhena F. U., Albers, Joachim, Seidel, Philipp, Brandt, Laura P., Hejhal, Tomas, Busenhart, Philipp, Röhner, Niklas, Zodel, Kyra, Fritsch, Kornelia, Wild, Peter Johannes, Duyster, Justus, Fritsch, Ralph, Brummer, Tilman, Frew, Ian, Catalano, Antonella, Adlesic, Mojca, Kaltenbacher, Thorsten, Klar, Rhena F. U., Albers, Joachim, Seidel, Philipp, Brandt, Laura P., Hejhal, Tomas, Busenhart, Philipp, Röhner, Niklas, Zodel, Kyra, Fritsch, Kornelia, Wild, Peter Johannes, Duyster, Justus, Fritsch, Ralph, Brummer, Tilman, and Frew, Ian

Abstract

Simple Summary: Mutations in RAS-family genes frequently cause different types of human cancers. Inhibitors of the MEK (mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase) protein kinases that function downstream of RAS proteins have shown some clinical benefits when used for the treatment of these cancers, but drug resistance frequently emerges. Here we show that combined treatment with MEK and ERK inhibitors blocks the emergence of resistance to either drug alone. However, if cancer cells have already developed resistance to MEK inhibitors or to ERK inhibitors, the combined therapy is frequently ineffective. These findings imply that these inhibitors should be used together for cancer therapy. We also show that drug resistance involves complex patterns of rewiring of cellular kinase signaling networks that do not overlap between each different cancer cell line. Nonetheless, we show that MAP4K4 is required for efficient cell proliferation in several different MEK/ERK inhibitor resistant cancer cell lines, uncovering a potential new therapeutic target. Abstract: Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic HrasG12V-driven undifferentiated pleomorphic sarcoma metastasis and of KrasG12D-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an HrasG12V-driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an abse

Published
2021

8. Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition

Author

Catalano, Antonella, primary, Adlesic, Mojca, additional, Kaltenbacher, Thorsten, additional, Klar, Rhena F. U., additional, Albers, Joachim, additional, Seidel, Philipp, additional, Brandt, Laura P., additional, Hejhal, Tomas, additional, Busenhart, Philipp, additional, Röhner, Niklas, additional, Zodel, Kyra, additional, Fritsch, Kornelia, additional, Wild, Peter J., additional, Duyster, Justus, additional, Fritsch, Ralph, additional, Brummer, Tilman, additional, and Frew, Ian J., additional

Published
2021
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