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Inhibitors of Deacetylases Suppress Oncogenic KIT Signaling, Acetylate HSP90, and Induce Apoptosis in Gastrointestinal Stromal Tumors

¹ Sarcoma Center, West German Cancer Center, University of Essen, Medical School, Essen, Germany; ² Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute and ³ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁴ Department of Surgery, University Hospital Mainz, Mainz, Germany; and ⁵ Division of Human Health and Medical Science, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi, Japan

Requests for reprints: Sebastian Bauer, Department of Internal Medicine/Cancer Research (West German Cancer Center), Hufelandstr. 55, 45122 Essen, Germany. Phone: 215-440-9300; Fax: 215-440-9354; E-mail: sebastian.bauer{at}uni-due.de.

Key Words: KIT • HDAC • SAHA • gastrointestinal neoplasm • sarcoma • GIST

Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDACI was seen in KIT-positive but not in KIT-negative GIST cell lines, suggesting that HDACI activity is mainly conferred by targeting oncogenic KIT. KIT activity, expression, and activation of downstream pathways were strongly inhibited by several HDACI (SAHA, LBH589, VPA, trichostatin A, and NaButyrate). SAHA and LBH589 induced apoptosis in KIT-positive GIST, and strong synergism with imatinib was observed at low concentrations of SAHA and LBH589. Mechanistically, treatment with HDACI reduced KIT mRNA transcript levels and led to strong acetylation of HSP90, interfering with its activity as KIT chaperone. These results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity. [Cancer Res 2009;69(17):6941–50]