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Verfasst von:Boichuk, Sergei [VerfasserIn]   i
 Korzeniewski, Nina [VerfasserIn]   i
Titel:Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors
Verf.angabe:Sergei Boichuk, Derek J. Lee, Keith R. Mehalek, Kathleen R. Makielski, Agnieszka Wozniak, Danushka S. Seneviratne, Nina Korzeniewski, Rolando Cuevas, Joshua A. Parry, Matthew F. Brown, James Zewe, Takahiro Taguchi, Shin-Fan Kuan, Patrick Schöffski, Maria Debiec-Rychter, and Anette Duensing
E-Jahr:2014
Jahr:January 2, 2014
Umfang:14 S.
Fussnoten:Gesehen am 24.09.2020
Titel Quelle:Enthalten in: Cancer research
Ort Quelle:Philadelphia, Pa. : AACR, 1916
Jahr Quelle:2014
Band/Heft Quelle:74(2014), 4, Seite 1200-1213
ISSN Quelle:1538-7445
Abstract:Most gastrointestinal stromal tumors (GIST) are caused by oncogenic KIT or platelet-derived growth factor receptor activation, and the small molecule kinase inhibitor imatinib mesylate is an effective first-line therapy for metastatic or unresectable GIST. However, complete remissions are rare and most patients ultimately develop resistance, mostly because of secondary mutations in the driver oncogenic kinase. Hence, there is a need for novel treatment options to delay failure of primary treatment and restore tumor control in patients who progress under therapy with targeted agents. Historic data suggest that GISTs do not respond to classical chemotherapy, but systematic unbiased screening has not been performed. In screening a compound library enriched for U.S. Food and Drug Administration (FDA)-approved chemotherapeutic agents (NCI Approved Oncology Drugs Set II), we discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT expression and/or intrinsic DNA damage response defects, explaining their activity in GIST. Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDA-approved chemotherapeutic agents, with immediate implications for encouraging their clinical exploration. Cancer Res; 74(4); 1200-13. ©2014 AACR.
DOI:doi:10.1158/0008-5472.CAN-13-1955
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-13-1955
 Volltext: https://cancerres.aacrjournals.org/content/74/4/1200
 DOI: https://doi.org/10.1158/0008-5472.CAN-13-1955
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:1733683720
Verknüpfungen:→ Zeitschrift

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