Abstract
BackgroundImatinib shows limited efficacy in patients with gastrointestinal stromal tumors (GISTs) carrying secondary KIT mutations. HQP1351, an orally bioavailable multikinase BCR-ABL inhibitor, is currently in clinical trials for the treatment of T315I mutant chronic myelogenous leukemia (CML), but the potential application in imatinib-resistant GISTs carrying secondary KIT mutations has not been explored.MethodsThe binding activities of HQP1351 with native or mutant KIT were first analyzed. Imatinib-sensitive GIST T1 and imatinib-resistant GIST 430 cells were employed to test the in vitro antiproliferative activity. Colony formation assay, cell migration assay and cell invasion assay were performed to evaluate the clonogenic, migration and invasion ability respectively. Flow cytometry and western blot analysis were used to detect cell apoptosis, cell cycle and signaling pathway. In vivo antitumor activity was evaluated in mouse xenograft models derived from GIST cell lines.ResultsHQP1351 potently inhibited both wild-type and mutant KIT kinases. In both imatinib-resistant and sensitive GIST cell lines, HQP1351 exhibited more potent or equivalent antiproliferative activity compared with ponatinib, a third generation BCR-ABL and KIT inhibitor. HQP1351 led to more profound inhibition of cell colony formation, cell migration and invasion, cell cycle arrest and cell apoptosis than ponatinib. Furthermore, HQP1351 also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib. Finally, in xenograft tumor models derived from imatinib-resistant GIST cancer cell lines, HQP1351 exhibited antitumor activity superior to ponatinib.ConclusionsCollectively, our in vitro and in vivo results suggest that the therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in clinical trials.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors that often develop drug resistance during routine first-line chemotherapy and radiotherapy [1]
Collectively, our in vitro and in vivo results suggest that the therapeutic application of HQP1351 in imatinib-resistant gastrointestinal stromal tumors (GIST) patients deserves further investigation in clinical trials
Through preclinical models, we investigated the ability of HQP1351 to overcome drug resistance for the treatment of GISTs
Summary
Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors that often develop drug resistance during routine first-line chemotherapy and radiotherapy [1]. Gain-of-function mutation at KIT is found in around 75% of GISTs [6, 7] These primary activation mutations are usually located in KIT exons 9 and 11. Imatinib (Gleevec), a small molecule inhibitor against BCR-ABL, KIT, and PDGFR, shows the inhibitory effect on GISTs and has been approved for KIT-positive GIST as the first-line treatment. It is used to treat imatinib-resistant GIST patients, as it is able to inhibit KIT mutation in the ATP binding pocket [10]. Imatinib shows limited efficacy in patients with gastrointestinal stromal tumors (GISTs) carrying secondary KIT mutations. HQP1351, an orally bioavailable multikinase BCR-ABL inhibitor, is currently in clinical trials for the treatment of T315I mutant chronic myelogenous leukemia (CML), but the potential application in imatinibresistant GISTs carrying secondary KIT mutations has not been explored
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