Mutations in the FMS-like tyrosine kinase 3 () gene are often present in newly diagnosed acute myeloid leukemia (AML) patients with an incidence rate of approximately 30%. Recently, many FLT3 inhibitors have been developed and exhibit positive preclinical and clinical effects against AML. However, patients develop resistance soon after undergoing FLT3 inhibitor treatment, resulting in short durable responses and poor clinical effects. This review will discuss the main mechanisms of resistance to clinical FLT3 inhibitors and summarize the emerging strategies that are utilized to overcome drug resistance. Basically, medicinal chemistry efforts to develop new small-molecule FLT3 inhibitors offer a direct solution to this problem. Other potential strategies include the combination of FLT3 inhibitors with other therapies and the development of multitarget inhibitors. It is hoped that this review will provide inspiring insights into the discovery of new AML therapies that can eventually overcome the resistance to current FLT3 inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.0c01851 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies.
Leukemia
January 2025
The Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
The FLT3 gene frequently undergoes mutations in acute myeloid leukemia (AML), with internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations (PMs) being most common. Recently, PMs and deletions in the FLT3 juxtamembrane domain (JMD) have been identified, but their biological and clinical significance remains poorly understood. We analyzed 1660 patients with de novo AML and found FLT3-JMD mutations, mostly PMs, in 2% of the patients.
View Article and Find Full Text PDFUnveiling unexpected adverse events: post-marketing safety surveillance of gilteritinib and midostaurin from the FDA Adverse Event Reporting database.
Ther Adv Drug Saf
January 2025
Department of Pharmacy, Daping Hospital, Army Medical University, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
Background: Gilteritinib and midostaurin are FLT3 inhibitors that have made significant progress in the treatment of acute myeloid leukemia. However, their real-world safety profile in a large sample population is incomplete.
Objectives: We aimed to provide a pharmacovigilance study of the adverse events (AEs) associated with gilteritinib and midostaurin through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database.
Evaluation of the Toxicity and Outcomes of the Combination of Midostaurin and CLAG-M in Patients With FLT3-Mutated Acute Myeloid Leukemia (AML): A Multicenter Retrospective Analysis.
Ann Pharmacother
January 2025
Department of Hematologic Malignancies, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Background: Addition of midostaurin to standard "7+3" (cytarabine and anthracycline) significantly prolongs overall and event-free survival. At University of Washington/Fred Hutchinson Cancer Center (UW/FHCC), the standard regimen for newly diagnosed (ND) and relapsed/refractory (R/R) AML is cladribine, high-dose cytarabine, GCSF, and mitoxantrone (CLAG-M); midostaurin is added if FLT3-mutated. There is limited data on the use of FLT3-inhibitors with high-dose cytarabine regimens in AML.
View Article and Find Full Text PDFAdvances and Challenges in Quizartinib-Based FLT3 Inhibition for Acute Myeloid Leukemia: Mechanisms of Resistance and Prospective Combination Therapies.
Eur J Haematol
January 2025
Hematology Unit, Azienda Ospedaliera Annunziata, Cosenza, Italy.
FLT3 mutations are among the most common genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Significant advancements have been made in developing FLT3 inhibitors (FLT3Is), such as quizartinib, which have improved treatment outcomes in both newly diagnosed and relapsed/refractory AML. Resistance to FLT3Is remains a major clinical challenge, driven by diverse mechanisms including FLT3 point mutations, cellular escape pathways, and the influence of the bone marrow microenvironment.
View Article and Find Full Text PDFFLT3 inhibitors induce p53 instability, driven by STAT5/MDM2/p53 competitive interactions in acute myeloid leukemia.
Cancer Lett
January 2025
Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China. Electronic address:
Article Synopsis
- FLT3 mutations are common in AML, making them a key target for therapy, but resistance to FLT3 inhibitors is a significant challenge.
- Tyrosine kinase inhibitors (TKIs) promote p53 degradation in FLT3-ITD AML cells through mechanisms involving STAT5 and MDM2, disrupting p53's role as a tumor suppressor.
- Using MDM2 inhibitors alongside TKIs can stabilize p53 levels, enhancing the effectiveness of treatments and suggesting a promising combination approach for AML therapy.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!