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|Ref Type||Journal Article|
|Authors||Liu X, Wang G, Yan X, Qiu H, Min P, Wu M, Tang C, Zhang F, Tang Q, Zhu S, Qiu M, Zhuang W, Fang DD, Zhou Z, Yang D, Zhai Y|
|Title||Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors.|
|Journal||Cell & bioscience|
|Abstract Text||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 imatinib-resistant GISTs carrying secondary KIT mutations has not been explored.The 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.HQP1351 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.Collectively, 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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|HQP1351||HQP 1351|HQP-1351|GZD824 dimesylate|GZD824|Olverembatinib||ABL1 Inhibitor 6 FGFR1 Inhibitor 24 FLT3 Inhibitor 57 KIT Inhibitor 52 PDGFR-alpha Inhibitor 9||GZD824 (HQP1351) is a third-generation BCR-ABL inhibitor and multikinase inhibitor that inhibits KIT, ABL1, FGFR1, FLT3, and PDGFRA (PMID: 32247263), which potentially induces apoptosis, and inhibits tumor cell growth, migration, and invasion (PMID: 31673329).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KIT V560_L576del KIT V654A||gastrointestinal stromal tumor||sensitive||HQP1351||Preclinical - Cell line xenograft||Actionable||In a preclinical study, HQP1351 treatment inhibited Kit downstream signalling, resulted in cell cycle arrest and apoptosis in a Gleevec (imatinib)-resistant gastrointestinal stromal tumor (GIST) cell line harboring KIT V560_L576del and V654A in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 31673329).||31673329|
|KIT V560_Y578del||gastrointestinal stromal tumor||sensitive||HQP1351||Preclinical - Cell line xenograft||Actionable||In a preclinical study, HQP1351 treatment inhibited Kit activity and proliferation of a gastrointestinal stromal tumor (GIST) cell line harboring KIT V560_Y578del in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 31673329).||31673329|