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.