Bortezomib enhances the therapeutic efficacy of dasatinib by promoting c-KIT internalization-induced apoptosis in gastrointestinal stromal tumor cells

摘要: Dasatinib-based therapy is often used as a second-line therapeutic strategy for imatinib-resistance gastrointestinal stromal tumors (GISTs); however, acquired aberrant activation of dasatinib target proteins, such as c-KIT and PDGFR13, attenuates the therapeutic efficiency of dasatinib. Combination therapy which inhibits the activation of dasatinib target proteins may enhance the cytotoxicity of dasatinib in GISTs. Bortezomib, a proteasome inhibitor, significantly inhibited cell viability and promoted apoptosis of dasatinib-treated GIST-TI cells, whereas GIST-TI cells showed little dasatinib cytotoxicity when treated with dasatinib alone, as the upregulation of c-KIT caused by dasatinib itself interfered with the inhibition of c-KIT and PDGFRI3 phosphorylation by dasatinib. Bortezomib induced internalization and degradation of c-KIT by binding c-KIT to Cbl, an E3 ubiquitin-protein ligase, and the subsequent release of Apaf-1, which was originally bound to the c-KIT-Hsp903-Apaf-1 complex, induced primary apoptosis in GISTTI cells. Combined treatment with bortezomib plus dasatinib caused cell cycle arrest in the G1 phase through inactivation of PDGFRP and promoted bortezomib-induced apoptosis in GIST-TI cells. Our data suggest that combination therapy exerts better efficiency for eradicating GIST cells and may be a promising strategy for the future treatment of GISTs. (C) 2015 Elsevier Ireland Ltd. All rights reserved.