Our findings suggest that combinatorial inhibition of CK2 and KIT warrants evaluation as a novel therapeutic strategy in GIST, especially in imatinib-resistant GIST.
This case illustrates that knowing the specific type of KIT mutations may uncover resistance of certain GIST's to TKIs, necessitating more targeted and alternative therapy.
Additional genetic events including RB1, SMARCB1, and MAX except secondary KIT/PDGFRA mutations are the most common for GISTs to evolve into resistant disease.
Most gastrointestinal stromal tumours (GIST) are driven by activating oncogenic mutations of KIT/PDGFRA, which provide a compelling therapeutic target.
GISTs with predominant epithelioid cell morphology may pose a diagnostic dilemma therefore in all suspected cases of GIST, immunocytochemistry for c-Kit and/or DOG1 should be employed on cell block preparations to confirm the diagnosis of GIST.
ETV1 is a member of the ETS family of transcription factors, already known oncogenic drivers in Ewing sarcoma, prostate cancer and gastrointestinal stromal tumors, but not in gliomas.
Coordinated inhibition of CK2 and KIT by CX4945 (or CK2 shRNA) and imatinib, respectively, leads to increased apoptosis, anti-proliferative effects and cell cycle arrest and decreased p-AKT and p-S6 expression, migration and invasiveness in all GIST cell lines compared with either intervention alone, indicating additive effects of inhibiting these two important regulators of GIST biology.
Our previous studies showed that CDC37, regulated by casein kinase 2 (CK2), is a crucial HSP90 cofactor for KIT oncogenic function and a promising and more selective therapeutic target in GIST.
18F-FDG PET/CT seems to be an accurate method for detection and localization of local and distant recurrence in GIST with good sensitivity and specificity and significant impact on clinical decision-making.
Additional genetic events including RB1, SMARCB1, and MAX except secondary KIT/PDGFRA mutations are the most common for GISTs to evolve into resistant disease.
Alterations in cell cycle regulation-associated genes, such as genetic mutations and MYC copy number gain, may promote primary progression from low-grade GISTs to high-grade tumors by regulating tumor cell proliferation.
Additional genetic events including RB1, SMARCB1, and MAX except secondary KIT/PDGFRA mutations are the most common for GISTs to evolve into resistant disease.
All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4.
Our findings suggest that combinatorial inhibition of CK2 and KIT warrants evaluation as a novel therapeutic strategy in GIST, especially in imatinib-resistant GIST.
Treatment with a specific CK2 inhibitor, CX4945, leads to CDC37 dephosphorylation and inhibits KIT signalling in imatinib-sensitive and in imatinib-resistant GIST cell lines.
We tested the activity of avapritinib, a potent and highly selective inhibitor of mutated KIT and PDGFRA, in three patient-derived xenograft (PDX) GIST models carrying different <i>KIT</i> mutations, with differential sensitivity to standard TKI.<b>Experimental Design:</b> NMRI <i>nu/nu</i> mice (<i>n</i> = 93) were transplanted with human GIST xenografts with <i>KIT</i> exon 11+17 (UZLX-GIST9 <i>