GIST research in the Duensing Lab
Gastrointestinal stromal tumors (GISTs) are a prototypical example of a solid tumor entity that was fatal in the past but that can now be successfully treated with a novel class of drugs, called small molecule protein kinase inhibitors. Imatinib mesylate (Gleevecâ„¢) is the first and most prominent inhibitor that belongs to this group.
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It targets the KIT and PDGFRA protein kinases, which are mutated in GISTs and drives tumorigenesis. Imatinib rapidly shuts down aberrant KIT and PDGFRA signaling activity, but it needs to be emphasized that the precise molecular events that lead to GIST cell eradication are unknown. Elucidating these mechanisms would not only allow to develop a â€œbetter imatinibâ€ that is even more effective and does not lead to therapy resistance, a problem that is more and more encountered in GIST patients. Moreover, understanding the mode of action of imatinib and why it is so effective in GISTs will be instrumental to develop novel small molecule protein kinase inhibitors and to identify other proteins that can be targeted therapeutically.
Towards these aims, we have begun to study the role of a protein involved in DNA damage repair signaling, histone H2AX. We found a massive and hitherto unrecognized induction of histone H2AX expression in GIST cells treated with imatinib. This upregulation was found to correspond with GIST cell death, and we discovered that H2AX is directly causing this process in a manner that is not necessarily dependent on its well-established role in DNA damage repair signaling. We are also currently investigating how KIT signaling interferes with H2AX levels and how imatinib treatment causes its upregulation. Moreover, we are studying how H2AX can stimulate GIST cell death. Those experiments will be complemented by efforts to identify additional signaling molecules in drug-induced GIST cell apoptosis.
Our ultimate goal is to develop a framework for future translational studies to improve the therapeutic options for GIST patients.