Despite significant treatment advances over the past decade, metastatic
gastrointestinal stromal tumor (GIST) remains largely incurable.
Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, "drug repurposing" or "repositioning," has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds,
auranofin (
Ridaura) and
fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including
imatinib-resistant cells. One of the most notable drug hits,
auranofin, an oral,
gold-containing agent approved by the FDA in 1985 for the treatment of
rheumatoid arthritis, was found to inhibit
thioredoxin reductase activity and induce
reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with
auranofin was independent of
imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that
auranofin has an established safety profile in patients, these findings suggest for the first time that
auranofin may have clinical benefit for patients with GIST, particularly in those suffering from
imatinib-resistant and recurrent forms of this disease.