scholarly journals Inhibition of PI3K and MAPK pathways along with KIT inhibitors as a strategy to overcome drug resistance in gastrointestinal stromal tumors

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0252689
Author(s):  
Anu Gupta ◽  
Shuang Ma ◽  
Kepeng Che ◽  
Ajaybabu V. Pobbati ◽  
Brian P. Rubin
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinases ◽  
Gastrointestinal Stromal Tumors ◽  
Mapk Signaling ◽  
Resistance Mutations ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Activating Mutations ◽  
Mapk Pathways ◽  
Induced Apoptosis

Activating mutations in KIT/PDGFRA receptor tyrosine kinases drive gastrointestinal stromal tumors (GIST). KIT/PDGFRA inhibitors, such as imatinib do not evoke an effective cytocidal response, leaving room for quiescence and development of multiple secondary resistance mutations. As the majority of the secondary resistance clones activate PI3K and MAPK pathways, we investigated whether combined targeting of KIT/PI3K/MAPK (KPM) pathways overcomes drug resistance and quiescence in GIST cells. We monitored the proliferation of imatinib–sensitive and–resistant GIST cell lines after treating them with various combinations of drugs to inhibit KPM pathways. Cytocidal response was evaluated through proliferation, apoptosis and colony outgrowth assays. Combined inhibition of KPM signaling pathways using a KPM inhibitor cocktail decreased the survival of drug-resistant GIST cells and dramatically reduced their proliferation. Downstream pathway analysis showed that the residual PI3K/MAPK signaling observed after KIT inhibitor treatment plays a role in mediating quiescence and drug resistance. The KPM inhibitor cocktail with sunitinib or regorafenib effectively induced apoptosis and prevented colony outgrowth after long-term drug removal, suggesting that it can be used as an effective strategy against quiescence and drug resistance in metastatic GIST.

MOLECULAR AND GENETIC FEATURES OF GASTROINTESTINAL STROMAL TUMORS

2019 ◽  
Vol 65 (1) ◽  
pp. 69-76
Author(s):  
Foat Akhmetzyanov ◽  
Sergey Petrov ◽  
Dinar Khalikov
Keyword(s):  
Tyrosine Kinases ◽  
Gastrointestinal Stromal Tumors ◽  
Mutational Analysis ◽  
Scientific Information ◽  
Prognostic Significance ◽  
Driver Mutations ◽  
Stromal Tumors ◽  
Activating Mutations ◽  
Genetic Features ◽  
Cells Of Cajal

In this review presented the most relevant scientific information on the molecular and genetic features of gastrointestinal stromal tumors (GISTs). GISTs is a heterogeneous group of mesenchymal neoplasms of the gastrointestinal tract, which according to modern ideas originate from the interstitial cells of Cajal. It was found that this disease is largely somatic mutations: in the overwhelming majority of cases, activating mutations in kit or PDGFRA genes that encode effector tyrosine kinases are found in tumor cells. Constitutive activation of these enzymes triggers a complex cascade of intracellular reactions, the result of which is the enhancement of cell proliferation and tumor growth. In the absence of the above-mentioned driver mutations, the GISTs is referred to as a “wild type”. The profile of mutations affects the aggressiveness of the GISTs flow and the sensitivity to target antitumor drugs. Thus, carrying out a mutational analysis in the case of a GISTs is of great prognostic significance.

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.

Use of ponatinib to inhibit kinase mutations associated with drug-resistant gastrointestinal stromal tumors (GIST).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10509-10509 ◽  
Author(s):  
Michael C. Heinrich ◽  
Jonathan A. Fletcher ◽  
Rana Anjum ◽  
Cesar Serrano-Garcia ◽  
Sadanand Vodala ◽  
...  
Keyword(s):  
Cell Lines ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Activity ◽  
Binding Pocket ◽  
Drug Resistant ◽  
Line Treatment ◽  
Resistance Mutations ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Exon 11

10509 Background: Ponatinib (PO) is a multi-targeted tyrosine kinase inhibitor with potent pan-BCR-ABL activity that has recently been approved for treatment of CML and Ph+ ALL. PO also inhibits the kinase activity of KIT. Approximately 80% of gastrointestinal stromal tumors (GIST) contain primary activating KIT mutations, the majority of which cluster in exon 11. Imatinib (IM) is approved for the 1st line treatment of GIST; however, patients frequently relapse due to the acquisition of secondary resistance mutations located in either the KIT ATP-binding pocket or the activation (A) loop. Sunitinib (SU) is approved for 2nd line treatment of GIST but does not effectively inhibit A-loop mutants. Here we explored the activity of PO against major primary and secondary KIT mutants found in GIST. Methods: The drug sensitivity of KIT mutants was determined using engineered Ba/F3 cells harboring mutant forms of KIT exon 11 with or without ATP binding pocket or A-loop mutations. The abilities of PO, IM, SU, and regorafenib (RE) to inhibit viability and/or KIT kinase activity were compared using this system as well as an isogenic CHO cell system. We also profiled these same drugs using a panel of GIST cell lines, including cell lines with IM-resistant secondary KIT mutations. Results: In all in vitro systems, PO potently inhibited KIT exon 11 mutant kinases, with an IC50 of < 30 nM. PO also potently inhibited a range of secondary KIT mutants, including multiple A-loop mutant kinases. PO induced substantial tumor regression in Ba/F3 tumor models expressing a KIT exon 11 mutant with or without an A-loop mutation (D816H). Using GIST cell lines, PO inhibited the viability of those harboring primary KIT exon 11 and secondary resistance mutations more effectively than IM, SU, and RE. Importantly, in patients dosed once daily with 45 mg ponatinib, plasma concentrations achieved are predicted to lead to inhibition of all KIT mutants tested with the possible exception of V654A. Conclusions: PO potently inhibits the majority of clinically relevant KIT mutant kinases and has a broader spectrum of activity compared to IM, SU, or RE. Based on these data, a phase 2 study of PO in drug-resistant GIST is being initiated.

scholarly journals Mechanisms of the resistance of gastrointestinal stromal tumors to imatinib

2018 ◽  
Vol 99 (6) ◽  
pp. 959-965
Author(s):  
A R Galembikova ◽  
S V Boichuk
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Gastrointestinal Stromal Tumors ◽  
Target Therapy ◽  
Acquired Resistance ◽  
Mesenchymal Tumors ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Mutational Status

The review describes the modern concepts of the primary and secondary (acquired) resistance of gastrointestinal stromal tumors to the targeted drug imatinib. Gastrointestinal stromal tumors are the mesenchymal tumors of gastrointestinal tract that originate from interstitial cells of Cajal or their stem cell precursors. Up to 85 % of gastrointestinal stromal tumors have the mutations of KIT gene that lead to ligand-independent activation of this tyrosine kinase. Imatinib is an inhibitor of KIT tyrosine kinase which is hyperexpressed in 70-85 % of cases on the cell membrane of gastrointestinal stromal tumors. Despite the high effectiveness of imatinib in gastrointestinal stromal tumors, up to 15 % of patients do not respond to this therapy, and over 50 % of patients acquire the resistance to this drug 2 years after initiation of target therapy with imatinib. The mechanisms of primary resistance include basically the mutational status of KIT, PDGFRA and, rarely, mutations of SDH, NF1, BRAF, PI3K3CA, CBL, and KRAS. The mechanisms of secondary resistance of tumor cells to imatinib are not restricted to the secondary mutations of KIT and PDGFRA, but also might be due to the loss of KIT expression associated by overexpression of the alternative receptor- and non-receptor tyrosine kinases, such as MET, AXL, FGFR2α, FAK, etc. Alternative mechanisms of acquired resistance might be due to the mutations of BRAF gene.

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.

14-3-3 Integrates Pro-Survival Signals in Hematopoietic Cells Transformed by Diverse Leukemogenic Tyrosine Kinases, and Represents a Common Target.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1138-1138
Author(s):  
Shaozhong Dong ◽  
Sumin Kang ◽  
Ting-lei Gu ◽  
Sean Kardar ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Nuclear Localization ◽  
Tyrosine Kinases ◽  
Mapk Signaling ◽  
Hematopoietic Malignancies ◽  
Clinical Resistance ◽  
Induced Apoptosis ◽  
In Cells ◽  
Survival Signals

Abstract Constitutively activated tyrosine kinases associated with recurrent chromosomal abnormalities play an essential role in the pathogenesis and disease progression of a variety of hematopoietic malignancies. Selective tyrosine kinase inhibitors such as imatinib are effective in treating some forms of leukemia such as t(9;22) CML associated with expression of BCR-ABL fusion tyrosine kinase. However, they are not curative and clinical resistance may develop, prompting the design of alternate and/or complementary therapeutic strategies. To better understand the signaling properties of constitutively activated tyrosine kinases associated with different hematopoietic malignancies, we examined whether BCR-ABL, FLT3-ITD, NPM-ALK, TEL-PDGFbetaR, TEL-FGFR3 and ZNF198-FGFR1 activate the same set of signaling pathways. We found that they all activated AKT and MAPK signaling pathways. Activated AKT resulted in phosphorylation of FOXO3a at Thr-32 but not BAD at Ser-136, whereas activated MAPK led to phosphorylation of BAD at Ser-112. These phosphorylated residues subsequently sequestered the pro-apoptotic FOXO3a and BAD to 14-3-3, suggesting that 14-3-3 integrates pro-survival signals from AKT and MAPK pathways. We utilized a peptide-based 14-3-3 competitive antagonist, R18 to disrupt 14-3-3/ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by these tyrosine kinases with significantly enhanced sensitivity compared to the control Ba/F3 cells. Moreover, doxycycline-induced expression of R18 significantly attenuated the disease latency and penetrance in mice induced by intravenous injection of representative ZNF198-FGFR1-transformed Ba/F3 cells. Co-immunoprecipitation experiments indicate that induced R18 expression disrupted interaction between 14-3-3 and FOXO3a, but not 14-3-3/BAD association. R18 induced apoptosis by rescuing the nuclear localization of FOXO3a and up-regulating FOXO3a transcription targets Bim and p27 in cells expressing ZNF198-FGFR1. Furthermore, fluorescent confocal microscopy revealed that expression of R18 generally resumed FOXO3a nuclear localization in cells transformed by the spectrum of diverse leukemogenic tyrosine kinases. Together, these data support a model that 14-3-3 functions as a general integrator of pro-survival signals in hematopoietic transformation induced by diverse leukemogenic fusion/mutant tyrosine kinases. Disrupting 14-3-3/ligand association may be a common and effective therapeutic strategy for hematopoietic neoplasms associated with these tyrosine kinases.

scholarly journals Detection of c-kit–Activating Mutations in Gastrointestinal Stromal Tumors by High-Resolution Amplicon Melting Analysis

2004 ◽  
Vol 122 (2) ◽  
pp. 206-216 ◽  
Author(s):  
Carlynn Willmore ◽  
Joseph A. Holden ◽  
Luming Zhou ◽  
Sheryl Tripp ◽  
Carl T. Wittwer ◽  
...  
Keyword(s):  
High Resolution ◽  
Gastrointestinal Stromal Tumors ◽  
Stromal Tumors ◽  
Activating Mutations ◽  
Melting Analysis

scholarly journals Recent advances in managing gastrointestinal stromal tumor

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1689 ◽  
Author(s):  
Florence Duffaud ◽  
Axel Le Cesne
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Platelet Derived Growth Factor ◽  
Proof Of Concept ◽  
Current Standard ◽  
Stromal Tumors ◽  
Concept Model ◽  
Activating Mutations ◽  
Effective Proof

Constitutive activating mutations inKITand platelet-derived growth factor receptor α (PDGFRα) are heavily involved in the pathobiology of gastrointestinal stromal tumors (GISTs). This disease has served as an effective “proof-of-concept” model for targeting gain-of-function kinase mutations in cancer. This review discusses the current standard of care in terms of pharmacotherapy in the management of localized and metastatic GISTs.

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