KIT wild-type

Newly diagnosed AML patients with AML1/ETO fusion had a poor response to frontline VEN/HMA treatment. When determining induction therapy for patients with AML1/ETO-positive AML, IC should be preferred over VEN/HM.

Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.

While SM can have a variety of clinical manifestations, including elevated tryptase level and mediator release symptoms, the presence of KIT D816V in the peripheral blood is a strong predictor of SM diagnosis. Persistently elevated serum tryptase without the KIT D816V mutation may suggest the likelihood of HaT, while only mediator release symptoms with normal serum tryptase and without the KIT mutation is a strong negative predictor of SM and HaT.

The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KIT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.

In comparison to parental GIST-T1, GIST-BSF1 treated with SCF displayed 4.3-29.3-fold higher GR50-values for all tested KIT inhibitors, except for sunitinib (1.4-fold) and nintedanib (3.1-fold)...GIST-BSF1 sublines with secondary mutations in-cis in both the ATP binding pocket (AP) and activation loop (AL) of KIT, called AP/AL mutations, display the same inhibitory profile towards ripretinib as seen in AP/AL mutations previously modelled in GIST-T1 (GR50 values for AP/AL mutants >20-fold higher than corresponding AL mutants)... GIST-BSF1 is the first KIT-WT, SCF-dependent GIST cell line, which allows study of the impact of KIT inhibitors on WT KIT. Reintroduction of KIT mutations leads to SCF-independent growth and yielded anticipated TKI profiles. This cell line platform allows the rapid validation of novel variants of KIT and other oncogenic kinases in a GIST-specific cellular background.

Table: 1977P Known and projected mutation distribution Conclusions By using the methods described, we were able to project the frequency of mutations in LRG registry patients and identified a higher frequency of unclassified mutations. A well-defined mutation can provide important information to optimize clinical decision-making, including diagnosis, prognosis, treatment selection, and monitoring treatment response.

Our results suggested that SPRY4 acts as negative feedback of primary KIT mutants in GISTs by inhibiting KIT expression and activation. It can increase the sensitivity of primary KIT mutants to imatinib. In contrast, secondary KIT mutants are resistant to the inhibition of SPRY4.

The two regressed melanomas of this cohort shared a 17-gene mutation signature, containing genes involved in antitumor immunity and several cell surface receptors. Even with this comprehensive genomic approach, a few cases remained driverless, suggesting that unrecognized drivers are hiding among passenger mutations.

P2, N=15, Completed, Grupo Espanol de Investigacion en Sarcomas | Recruiting --> Completed | N=39 --> 15

Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5.

This serves as an important lesson to keep the differential diagnosis broad when dealing with large cystic abdominal masses. The tumour was found to be KIT wild type, with a platelet-derived growth factor receptor alpha D842V mutation identified, conferring intrinsic resistance to imatinib.

Imatinib, one of the frequently used therapies for GIST, has demonstrated low sensitivity among KIT/PDGFRA wildtype GISTs... Utilizing NGS based CGP is a crucial step in understanding and identifying relevant biomarkers including tumor growth drivers to aid in the treatment decision for optimal patient outcomes. CGP provides relevant data for conducting a more accurate, individualized treatment plan for patients, and prevents patients from undergoing unnecessary therapies that will not work for their respective mutation. Furthermore, this approach accelerates adoption of precision oncology and aids future drug discovery and development programs specifically for GIST patients.

Surgery remains the principal treatment modality. Small intestine primary site and high mitotic count were associated with abbreviated OS.

Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy.