Topic Overview:
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with the majority caused by single activating mutations in the KIT receptor tyrosine kinase gene. Although more than 85 percent of patients with metastatic GIST can be effectively treated with the small-molecule kinase inhibitor imatinib mesylate (Gleevec®), complete responses are rare and most GIST patients eventually acquire resistance to imatinib. Although it is known that imatinib rapidly shuts down aberrant KIT kinase signaling activity, the precise molecular events that lead to GIST cell apoptosis are not well understood.

Dr. Duensing’s research focuses on elucidating the mechanisms that lead to imatinib-induced GIST cell apoptosis, work that is critical for the development of novel therapeutic options. Using human GIST cell lines as well as GISTs from transgenic mice with germline KIT mutations, Duensing showed that histone H2AX, a key protein involved in the DNA damage signaling pathway, is upregulated and mislocalized from chromatin in GIST cells following treatment with imatinib and that furthermore, H2AX upregulation is a direct cause of cellular apoptosis. Interestingly, this novel pro-apoptotic function of H2AX is not dependent on the DNA damage-associated function of histone H2AX. Based on observations that H2AX levels are held continuously low in GIST cells by the ubiquitin proteasome machinery, Duensing tested a second compound, the FDA-approved proteasome inhibitor bortezomib (Velcade®), for its efficacy in GIST. Indeed, bortezomib was found to be active against imatinib-sensitive and imatinib-resistant cells. Although treatment with bortezomib, like imatinib, leads to apoptosis through an increase in H2AX levels, Duensing found, surprisingly, that the ability of bortezomib to overcome imatinib resistance may come from its activation of a second mechanism—downregulation of KIT transcription. These results provide the rationale for future clinical trials involving bortezomib in GIST patients with imatinib-sensitive or -resistant tumors.

Future directions for the Duensing lab include further elucidation of the molecular biology of GISTs and other malignancies driven by oncogenically activated kinases and the discovery of pro-apoptotic pathways for the generation of novel and targeted therapeutic options.