Dasatinib overrides the differentiation blockage in a patient with mutant-<i>KIT</i> D816V positive CBFβ-MYH11 leukemia

Kampa-Schittenhelm, Kerstin M; Vogel, Wichard; Bonzheim, Irina; Fend, Falko; Horger, M.; Kanz, Lothar; Soekler, Martin; Schittenhelm, Marcus M

doi:10.18632/oncotarget.24376

Cited by 9 publications

(5 citation statements)

References 17 publications

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“…Genetic markers may be useful in predicting the prognosis of CBF AML and become new therapeutic targets, especially for those patients who cannot be cured by chemotherapy alone. In fact, targeting the highly expressed and frequently mutated KIT or FLT3 kinases, the addition of the second-generation tyrosine kinase inhibitor dasatinib to chemotherapy is currently being evaluated in clinical trials (35,38,61). The standard DA regimen combined with mutagen-specific targeted therapy, allogeneic hematopoietic stem cell transplantation and immunotherapy may reduce the recurrence of CBF AML and improve the cure rate (9).…”

Section: Discussionmentioning

confidence: 99%

Core binding factor acute myeloid leukemia: Advances in the heterogeneity of KIT, FLT3, and RAS mutations (Review)

Quan

Deng

2020

Mol Clin Oncol

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Core binding factor (CBF) is a heterodimer protein complex involved in the transcriptional regulation of normal hematopoietic process. In addition, CBF molecular aberrations represent approximately 20% of all adult Acute Myeloid Leukemia (AML) patients. Treated with standard therapy, adult CBF AML has higher complete remission (CR) rate, longer CR duration, and better prognosis than that of AML patients with normal karyotype or other chromosomal aberrations. Although the prognosis of CBF AML is better than other subtypes of adult AML, it is still a group of heterogeneous diseases, and the prognosis is often different. Recurrence and relapse-related death are the main challenges to be faced following treatment. Mounting research shows the gene heterogeneity of CBF AML. Therefore, to achieve an improved clinical outcome, the differences in clinical and genotypic characteristics should be taken into account in the evaluation and management of such patients, so as to further improve the risk stratification of prognosis and develop targeted therapy. The present article is a comprehensive review of the differences in some common mutant genes between two subtypes of CBF AML.

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Section: Discussionmentioning

confidence: 99%

Core binding factor acute myeloid leukemia: Advances in the heterogeneity of KIT, FLT3, and RAS mutations (Review)

Quan

Deng

2020

Mol Clin Oncol

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“… 29 Moreover, Kampa-Schittenhelm et al reported that dasatinib has an anti-leukemic effect on KIT-mutated CBF-AML. 30 Similarly, Heo et al demonstrated that dasatinib and radotinib induce AML cell death by targeting c-KIT both in vivo and in vitro. Therefore, dasatinib and radotinib could have a potential role in anti-leukemic therapy for c-KIT-positive AML patients.…”

Section: Leukemiamentioning

confidence: 97%

“…33 Several clinical trials have been performed to assess the utility of RTKs in c-KIT mutated AML. [29][30][31]131,132 Advani et al reported that imatinib can improve the outcome of newly diagnosed AML patients when it is used as a maintenance therapy after the completion of post-remission therapy. 29 Moreover, Kampa-Schittenhelm et al reported that dasatinib has an anti-leukemic effect on KIT-mutated CBF-AML.…”

Section: Dovepressmentioning

confidence: 99%

c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights

Abdellateif,

Bayoumi,

Mohammed

2023

OTT

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c-Kit is a type III receptor tyrosine kinase (RTK) that has an essential role in various biological functions including gametogenesis, melanogenesis, hematopoiesis, cell survival, and apoptosis. c-KIT aberrations, either overexpression or loss-of-function mutations, have been implicated in the pathogenesis and development of many cancers, including gastrointestinal stromal tumors, mastocytosis, acute myeloid leukemia, breast, thyroid, and colorectal cancer, making c-KIT an attractive molecular target for the treatment of cancers. Therefore, a lot of effort has been put into investigating the utility of tyrosine kinase inhibitors for the management of c-KIT mutated tumors. This review of the literature illustrates the role of c-KIT mutations in many cancers, aiming to provide insights into the role of TKIs as a therapeutic option for cancer patients with c-KIT aberrations. In conclusion, c-KIT is implicated in different types of cancer, and it could be a successful molecular target; however, proper detection of the underlying mutation type is required before starting the appropriate personalized therapy.

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“…While some KIT A-loop mutations (e.g., D816 alterations) render resistance to imatinib and sunitinib in patients with GIST, some agents (e.g., avapritinib and ponatinib) remain effective for such resistant cases [104,105]. Although the clinical role of KIT inhibitors in treatment of AML has not been established, there are a few clinical reports suggesting an anti-leukemic effect of KIT inhibitor (e.g., dasatinib) for KIT-mutated AML [106,107].…”

Section: Targeting Cd47mentioning

confidence: 99%

“…Kampa-Schittenhelm and colleagues reported 77-years-old patient with KIT D816Vmutated CBF-AML which relapsed after the first-line decitabine monotherapy [106]. Upon careful consideration and informed consent, he received a KIT inhibitor dasatinib as salvage chemotherapy.…”

Section: Targeting Cd47mentioning

confidence: 99%

Emerging Targeted Therapy for Specific Genomic Abnormalities in Acute Myeloid Leukemia

Chi

Minami

2022

IJMS

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We describe recent updates of existing molecular-targeting agents and emerging novel gene-specific strategies. FLT3 and IDH inhibitors are being tested in combination with conventional chemotherapy for both medically fit patients and patients who are ineligible for intensive therapy. FLT3 inhibitors combined with non-cytotoxic agents, such as BCL-2 inhibitors, have potential therapeutic applicability. The menin-MLL complex pathway is an emerging therapeutic target. The pathway accounts for the leukemogenesis in AML with MLL-rearrangement, NPM1 mutation, and NUP98 fusion genes. Potent menin-MLL inhibitors have demonstrated promising anti-leukemic effects in preclinical studies. The downstream signaling molecule SYK represents an additional target. However, the TP53 mutation continues to remain a challenge. While the p53 stabilizer APR-246 in combination with azacitidine failed to show superiority compared to azacitidine monotherapy in a phase 3 trial, next-generation p53 stabilizers are now under development. Among a number of non-canonical approaches to TP53-mutated AML, the anti-CD47 antibody magrolimab in combination with azacitidine showed promising results in a phase 1b trial. Further, the efficacy was somewhat better in patients with the TP53 mutation. Although clinical evidence has not been accumulated sufficiently, targeting activating KIT mutations and RAS pathway-related molecules can be a future therapeutic strategy.

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Dasatinib overrides the differentiation blockage in a patient with mutant-KIT D816V positive CBFβ-MYH11 leukemia

Cited by 9 publications

References 17 publications

Core binding factor acute myeloid leukemia: Advances in the heterogeneity of KIT, FLT3, and RAS mutations (Review)

Core binding factor acute myeloid leukemia: Advances in the heterogeneity of KIT, FLT3, and RAS mutations (Review)

c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights

Emerging Targeted Therapy for Specific Genomic Abnormalities in Acute Myeloid Leukemia

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