title: Drug repurposing identifies a synergistic combination therapy with imatinib mesylate for gastrointestinal stromal tumor.
abstract: Gastrointestinal stromal tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor imatinib mesylate radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time-to-progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly affected the overall survival of patients with advanced disease. We employed a novel, focused, drug-repurposing effort for GIST, including imatinib mesylate-resistant GIST, evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug-repurposing screen, we identified eight FDA-approved drugs, including fludarabine phosphate (F-AMP), that showed synergy with and/or overcame resistance to imatinib mesylate. F-AMP induces DNA damage, Annexin V, and caspase-3/7 activities as the cytotoxic effects on GIST cells, including imatinib mesylate-resistant GIST cells. F-AMP and imatinib mesylate combination treatment showed greater inhibition of GIST cell proliferation when compared with imatinib mesylate and F-AMP alone. Successful in vivo experiments confirmed the combination of imatinib mesylate with F-AMP enhanced the antitumor effects compared with imatinib mesylate alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with imatinib mesylate or for treatment of imatinib mesylate-refractory tumors.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Ziyan Y
authors.initials: ZY
authors.lastname: Pessetto
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Hirst
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas. Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, Kansas. University of Kansas Cancer Center, Kansas City, Kansas.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Weir
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas. University of Kansas Cancer Center, Kansas City, Kansas. agodwin@kumc.edu.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D058492:Drug Repositioning; D004357:Drug Synergism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D057166:High-Throughput Screening Assays; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D000068877:Imatinib Mesylate