SHORT COMMUNICATION Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients
نویسندگان
چکیده
Experimental Molecular Pathology, Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; Molecular Simulation Engineering Laboratory, DICAMP University of Trieste, Trieste, Italy; Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; Department of Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; Department of Clinical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy and IFOM, FIRC Institute of Molecular Oncology, Milan, Italy
منابع مشابه
Inactivity of imatinib in gastrointestinal stromal tumors (GISTs) harboring a KIT activation-loop domain mutation (exon 17 mutation pN822K)
The development of gastrointestinal stromal tumors (GISTs) is largely driven by mutations in the KIT and PDGFRα genes. Imatinib mesylate is an oral small molecular tyrosine kinase inhibitor that mainly targets abl, c-KIT, and PDGFRα. Imatinib achieves disease control in approximately 70%-85% of patients with advanced GIST, and the median progression-free survival is 20-24 months. The efficacy o...
متن کاملAcquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation.
Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 3...
متن کاملEstablishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors
Gastrointestinal stromal tumors (GISTs) with KIT or platelet-derived growth factor receptor alpha (PDGFRa) oncogenic driver gene mutations, respond to tyrosine kinase inhibitors (TKIs) including imatinib, sunitinib, and regorafenib. However, most patients develop TKI resistance; therefore, novel agents are required. We established three TKI-resistant GIST patient-derived xenograft (PDX) models ...
متن کاملCrosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance.
Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in ...
متن کاملCell line models identify different sensitivity of mutant forms of c-KIT to kinase inhibitory drugs and predict the response of patients to therapy.
Activating mutations in the receptor tyrosine kinase, c-KIT,were first described by Furitsu and colleagues (1) in a variant of the human mast cell line, HMC1. Two missense mutations resulting in single amino acid changes were observed: one in exon 11 leading to a V560G substitution in the intracellular juxtamembrane region, and the other in exon 17 causing a D816V substitution in the activation...
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