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| Verfasst von: | Melms, Johannes C. [VerfasserIn]  |
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| | Vallabhaneni, Sreeram [VerfasserIn] |
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| | Mills, Caitlin E. [VerfasserIn] |
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| | Yapp, Clarence [VerfasserIn] |
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| | Chen, Jia-Yun [VerfasserIn] |
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| | Morelli, Eugenio [VerfasserIn] |
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| | Waszyk, Patricia [VerfasserIn] |
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| | Kumar, Sushil [VerfasserIn] |
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| | Deming, Derrick [VerfasserIn] |
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| | Moret, Nienke [VerfasserIn] |
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| | Rodriguez, Steven [VerfasserIn] |
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| | Subramanian, Kartik [VerfasserIn] |
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| | Rogava, Meri [VerfasserIn] |
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| | Cartwright, Adam N. R. [VerfasserIn] |
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| | Luoma, Adrienne [VerfasserIn] |
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| | Mei, Shaolin [VerfasserIn] |
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| | Brinker, Titus Josef [VerfasserIn] |
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| | Miller, David M. [VerfasserIn] |
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| | Spektor, Alexander [VerfasserIn] |
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| | Schadendorf, Dirk [VerfasserIn] |
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| | Riggi, Nicolo [VerfasserIn] |
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| | Wucherpfennig, Kai W. [VerfasserIn] |
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| | Sorger, Peter K. [VerfasserIn] |
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| | Izar, Benjamin [VerfasserIn] |
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| Titel: | Inhibition of haspin kinase promotes cell-intrinsic and extrinsic antitumor activity |
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| Verf.angabe: | Johannes C. Melms, Sreeram Vallabhaneni, Caitlin E. Mills, Clarence Yapp, Jia-Yun Chen, Eugenio Morelli, Patricia Waszyk, Sushil Kumar, Derrick Deming, Nienke Moret, Steven Rodriguez, Kartik Subramanian, Meri Rogava, Adam N. R. Cartwright, Adrienne Luoma, Shaolin Mei, Titus J. Brinker, David M. Miller, Alexander Spektor, Dirk Schadendorf, Nicolo Riggi, Kai W. Wucherpfennig, Peter K. Sorger, and Benjamin Izar |
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| E-Jahr: | 2020 |
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| Jahr: | February 2020 |
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| Jahr des Originals: | 2019 |
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| Umfang: | 13 S. |
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| Illustrationen: | Illustrationen |
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| Fussnoten: | Published onlinefirst December 27, 2019 ; Gesehen am 02.04.2020 |
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| Titel Quelle: | Enthalten in: Cancer research |
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| Ort Quelle: | Philadelphia, Pa. : AACR, 1916 |
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| Jahr Quelle: | 2020 |
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| Band/Heft Quelle: | 80(2020), 4, Seite 798-810 |
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| ISSN Quelle: | 1538-7445 |
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| Abstract: | Patients with melanoma resistant to RAF/MEK inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small-molecule CX-6258 has potent activity against both RMi-sensitive (RMS) and -resistant (RMR) melanoma cell lines. Haspin kinase (HASPIN) was identified as a target of CX-6258. HASPIN inhibition resulted in reduced proliferation, frequent formation of micronuclei, recruitment of cGAS, and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In murine models, CX-6258 induced a potent cGAS-dependent type-I IFN response in tumor cells, increased IFNγ-producing CD8+ T cells, and reduced Treg frequency in vivo. HASPIN was more strongly expressed in malignant compared with healthy tissue and its inhibition by CX-6258 had minimal toxicity in ex vivo-expanded human tumor-infiltrating lymphocytes (TIL), proliferating TILs, and in vitro differentiated neurons, suggesting a potential therapeutic index for anticancer therapy. Furthermore, the activity of CX-6258 was validated in several Ewing sarcoma and multiple myeloma cell lines. Thus, HASPIN inhibition may overcome drug resistance in melanoma, modulate the immune environment, and target a vulnerability in different cancer lineages. - Significance: HASPIN inhibition by CX-6258 is a novel and potent strategy for RAF/MEK inhibitor-resistant melanoma and potentially other tumor types. HASPIN inhibition has direct antitumor activity and induces a favorable immune microenvironment. |
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| DOI: | doi:10.1158/0008-5472.CAN-19-2330 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext ; Verlag: https://doi.org/10.1158/0008-5472.CAN-19-2330 |
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| | Volltext: https://cancerres.aacrjournals.org/content/80/4/798 |
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| | DOI: https://doi.org/10.1158/0008-5472.CAN-19-2330 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| K10plus-PPN: | 169381806X |
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| Verknüpfungen: | → Zeitschrift |
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Inhibition of haspin kinase promotes cell-intrinsic and extrinsic antitumor activity / Melms, Johannes C. [VerfasserIn]; February 2020 (Online-Ressource)
