Ethyl-2-amino-pyrrole-3-carboxylates are active against imatinib-resistant gastrointestinal stromal tumors in vitro and in vivo

2019 ◽  
Vol 30 (5) ◽  
pp. 475-484
Author(s):  
Sergei Boichuk ◽  
Aigul Galembikova ◽  
Pavel Dunaev ◽  
Ekaterina Micheeva ◽  
Maria Novikova ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Stromal Tumors ◽  
Imatinib Resistant

scholarly journals Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xuechao Liu ◽  
Guangfeng Wang ◽  
Xianglei Yan ◽  
Haibo Qiu ◽  
Ping Min ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Trials ◽  
Cell Migration ◽  
Cell Lines ◽  
Gastrointestinal Stromal Tumors ◽  
Migration And Invasion ◽  
Stromal Tumors ◽  
Imatinib Resistant

Abstract Background 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. Methods 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. Results 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. Conclusions 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.

Synthesis, in vitro and in vivo evaluation of 18 F-fluoronorimatinib as radiotracer for Imatinib-sensitive gastrointestinal stromal tumors

2018 ◽  
Vol 57 ◽  
pp. 1-11 ◽  
Author(s):  
Martin Prause ◽  
Sabrina Niedermoser ◽  
Carmen Wängler ◽  
Clemens Decristoforo ◽  
Uwe Seibold ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
In Vivo Evaluation ◽  
Stromal Tumors

scholarly journals Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors

2019 ◽  
Vol 11 ◽  
pp. 175883591984975
Author(s):  
Feiyang Liu ◽  
Fengming Zou ◽  
Cheng Chen ◽  
Kailin Yu ◽  
Xiaochuan Liu ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Binding Modes ◽  
Primary Cells ◽  
Resistance Mutations ◽  
Preclinical Models ◽  
Gain Of Function ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Imatinib Resistant

Background: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells. Methods: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib. Results: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models. Conclusion: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.

scholarly journals A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity

2020 ◽  
Vol 10 (4) ◽  
pp. 234
Author(s):  
Mara Fornasarig ◽  
Daniela Gasparotto ◽  
Luisa Foltran ◽  
Michele Campigotto ◽  
Sara Lombardi ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Age Of Onset ◽  
Mesenchymal Tumors ◽  
Kit Mutation ◽  
Stromal Tumors ◽  
Activating Mutations ◽  
Imatinib Resistant

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs.

scholarly journals BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Jianfeng Mu ◽  
Xuezeng Sun ◽  
Zhipeng Zhao ◽  
Hao Sun ◽  
Pengda Sun
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Cellular Proliferation ◽  
Growth Factor Receptor ◽  
Mechanism Study ◽  
Baf Complex ◽  
Stromal Tumors ◽  
Factor Receptor Alpha ◽  
Gsk 3Β

AbstractGastrointestinal stromal tumors (GISTs) are primarily characterized by activating mutations of tyrosine kinase or platelet-derived growth factor receptor alpha. Although the revolutionary therapeutic outcomes of imatinib are well known, the long-term benefits of imatinib are still unclear. The effects of BRD9, a recently identified subunit of noncanonical BAF complex (ncBAF) chromatin remodeling complexes, in GISTs are not clear. In the current study, we evaluated the functional role of BRD9 in GIST progression. Our findings demonstrated that the expression of BRD9 was upregulated in GIST tissues. The downregulation or inhibition of BRD9 could significantly reduce cellular proliferation, and facilitates apoptosis in GISTs. BRD9 inhibition could promote PUMA-dependent apoptosis in GISTs and enhance imatinib activity in vitro and in vivo. BRD9 inhibition synergizes with imatinib in GISTs by inducing PUMA upregulation. Mechanism study revealed that BRD9 inhibition promotes PUMA induction via the TUFT1/AKT/GSK-3β/p65 axis. Furthermore, imatinib also upregulates PUMA by targeting AKT/GSK-3β/p65 axis. In conclusion, our results indicated that BRD9 plays a key role in the progression of GISTs. Inhibition of BRD9 is a novel therapeutic strategy in GISTs treated alone or in combination with imatinib.

Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

2006 ◽  
Vol 24 (29) ◽  
pp. 4764-4774 ◽  
Author(s):  
Michael C. Heinrich ◽  
Christopher L. Corless ◽  
Charles D. Blanke ◽  
George D. Demetri ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Molecular Mechanisms ◽  
Clonal Evolution ◽  
Clinical Problem ◽  
Primary Resistance ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Rnai Technology ◽  
Imatinib Resistant

Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways. Conclusion Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

scholarly journals Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST)

Oncotarget ◽  
2014 ◽  
Vol 6 (4) ◽  
pp. 1954-1966 ◽  
Author(s):  
Daruka Mahadevan ◽  
Noah Theiss ◽  
Carla Morales ◽  
Amy E. Stejskal ◽  
Laurence S. Cooke ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Combination Therapies ◽  
Stromal Tumors ◽  
Imatinib Resistant

scholarly journals A Phase I Study of Single-Agent Nilotinib or in Combination with Imatinib in Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors

2009 ◽  
Vol 15 (18) ◽  
pp. 5910-5916 ◽  
Author(s):  
George D. Demetri ◽  
Paolo G. Casali ◽  
Jean-Yves Blay ◽  
Margaret von Mehren ◽  
Jeffrey A. Morgan ◽  
...  
Keyword(s):  
Phase I ◽  
Gastrointestinal Stromal Tumors ◽  
Phase I Study ◽  
Single Agent ◽  
Stromal Tumors ◽  
Imatinib Resistant

Gastrointestinal Stromal Tumors (GISTs): From Science to Targeted Therapy

2008 ◽  
Vol 23 (2) ◽  
pp. 96-110 ◽  
Author(s):  
R. Sarmiento ◽  
P. Bonginelli ◽  
F. Cacciamani ◽  
F. Salerno ◽  
G. Gasparini
Keyword(s):  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Mesenchymal Tumors ◽  
Treatment Scenario ◽  
Stromal Tumors ◽  
Imatinib Resistant ◽  
Review Reports ◽  
Molecular Patterns

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs represent a distinct category of tumors characterized by oncogenic mutations of the KIT receptor tyrosine kinase in a majority of patients. KIT is useful not only for the diagnosis but also for targeted therapy of this disease. Imatinib, a tyrosine kinase inhibitor, is widely used in advanced and metastatic GISTs. This agent revolutionized the treatment strategy of advanced disease and is being tested in the neoadjuvant and adjuvant settings with encouraging results. New therapeutic agents like sunitinib have now been approved, enriching the treatment scenario for imatinib-resistant GISTs. The present review reports on the peculiar characteristics of this disease through its biology and molecular patterns, focusing on the predictive value of KIT mutations and their correlation with clinical outcome as well as on the activity of and resistance to approved targeted drugs.

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