We hypothesize that based on the allele frequency of SDHA and KIT mutations the tumor is best regarded as SDH-deficient GIST in which the SDHA mutation represents the most likely driver mutation.
SIGNIFICANCE: Expression and activity of mutant KIT is essential for driving the majority of GIST neoplasms, which can be therapeutically targeted using BET bromodomain inhibitors.
Gastrointestinal stromal tumors (GISTs), a type of mesenchymal tumor in the gastrointestinal tract, are believed to be closely associated with PDGFRA and C-KIT mutations.
Resistance to imatinib emerging in patients with GISTs after long-term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.
Compound 24 displays good antiproliferative effects against c-KITT670I mutant-driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy.
The nodule was resected in an enucleation procedure; subsequent histopathologic examination revealed a low-grade, spindled cell neoplasm with diffuse immunoreactivity for CD117 (cKit) and DOG1, diagnostic of GIST.
Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression.
The tumor was composed of two distinct phenotypes, a CD117 negative region with rhabdomyosarcomatous differentiation directly adjacent to a CD117 positive classic GIST region.
Currently, the main strategy to combat imatinib resistance is to switch to another tyrosine kinase inhibitor, because imatinib-resistant GIST is usually still oncogenically addicted to KIT/PDGFRA signaling.
KIT tyrosine kinase inhibitors provide targeted therapy for the underlying genetic mutation, and adjuvant therapy is indicated for patients who are at significant risk of relapse following GIST resection.
Luciferase assay data in GIST cells, generated using a construct containing all the three miR-221/222 binding sites, are consistent with KIT mRNA levels in GIST patients.
This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib.
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.