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

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.

Oncogenic receptor tyrosine kinase (RTK) translocations in a subset of quadruple wild-type gastrointestinal stromal tumors (GIST).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 11012-11012 ◽  
Author(s):  
Michael C. Heinrich ◽  
Guhyun Kang ◽  
Andrea Warrick ◽  
Christopher L. Corless ◽  
Carol Beadling
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Wild Type ◽  
Stromal Tumors

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

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.

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