Targeted therapies of gastrointestinal stromal tumors (GIST)--the next frontiers

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract and are caused by activating KIT or PDGFRA mutations. GISTs can be successfully treated with the small molecule kinase inhibitor imatinib mesylate (Gleevec, Novartis) with response rates of up to 85%. However, complete responses are rare, and most patients will develop imatinib resistance over time. Recent results have shown that although imatinib effectively stimulates apoptotic cell death in sensitive GIST cells, a considerable proportion of cells does not undergo apoptosis, but instead enters a state of quiescence. Quiescence is characterized by a reversible withdrawal from the cell division cycle, during which the cells remain alive and metabolically active. It is conceivable that quiescence not only plays a pivotal role in the emergence of residual disease but also in creating a pool of tumor cells that survive continuous small molecule therapy and may hence represent the "seeds" for the outgrowth of resistant clones. This review will summarize the current knowledge about GIST biology and treatment response to imatinib including the induction of cellular quiescence in GIST. In addition, we will highlight future strategies to design more effective treatment options to overcome these problems with an aim towards cure of this hitherto untreatable tumor entity.