REVIEW article
Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
This article is part of the Research TopicInnovative Strategies for the Discovery of New Therapeutic Targets in Cancer TreatmentView all 13 articles
Overcoming the sorafenib resistance mechanism in FLT3-mutated acute myeloid leukemia: Molecular Basis and New Targets
Provisionally accepted
- 1Jishou University School of Medicine, Jishou, China
- 2Jishou University First Affiliated Hospital, Jishou, China
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Acute myeloid leukemia (AML) originates from myeloid hematopoietic stem cells. Approximately 30% of patients exhibit FMS-like tyrosine kinase 3 (FLT3) mutations clinically, which are associated with a poor prognosis. FLT3 tyrosine kinase inhibitors (FLT3-TKIs), including sorafenib, demonstrate efficacy in FLT3-mutated AML, but resistance remains a significant challenge. However, various mechanisms have led to the rapid development of resistance to sorafenib treatment, including both primary and secondary drug resistance. Primary resistance refers to sorafenib's initial treatment failure due to redundant signaling pathways and tumor heterogeneity, while secondary resistance develops after prolonged therapy through new genetic mutations or activation of alternative pathways. This study systematically examines mechanisms of sorafenib resistance in AML, including tumor genetic changes and the bone marrow microenvironment. It outlines classic mechanisms, such as FLT3 functions, kinase mutations, and cellular signaling pathways, while also addressing gaps in knowledge regarding resistance driven by metabolic factors and the bone marrow environment. Furthermore, the paper explores novel FLT3 inhibitors and combination therapies, while outlining future directions for precision intervention through dynamic monitoring of clonal evolution. This review provides a comprehensive framework for understanding and addressing sorafenib resistance, offering insights into future therapeutic strategies for FLT3-mutated AML.
Keywords: FLT3 mutations, Sorafenib resistance, AML, targeted therapy, FLT3 inhibitors
Received: 25 Sep 2025; Accepted: 20 Nov 2025.
Copyright: © 2025 Peng, Li, Peng, Li and Song. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Kui Song, js_hematology@163.com
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