Title: Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors
Authors: Boichuk, Sergei ×
Lee, Derek J
Mehalek, Keith R
Makielski, Kathleen R
Wozniak, Agnieszka
Seneviratne, Danushka S
Korzeniewski, Nina
Cuevas, Rolando
Parry, Joshua A
Brown, Matthew F
Zewe, James
Taguchi, Takahiro
Kuan, Shih-Fan
Schoffski, Patrick
Schöffski, Patrick
Debiec-Rychter, Maria
Duensing, Anette #
Issue Date: 2014
Publisher: Waverly Press
Series Title: Cancer Research vol:74 issue:4 pages:1200-1213
Abstract: Most gastrointestinal stromal tumors (GISTs) are caused by oncogenic KIT or PDGFRA 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 due to 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 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.
ISSN: 0008-5472
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Experimental Oncology
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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