Zhou J, Chng WJ. Resistance to FLT3 inhibitors in acute myeloid leukemia: Molecular mechanisms and resensitizing strategies. World J Clin Oncol 2018; 9(5): 90-97 [PMID: 30254964 DOI: 10.5306/wjco.v9.i5.90]
Corresponding Author of This Article
Jianbiao Zhou, MD, PhD, Senior Scientist, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 28 Medical Drive, Singapore 119074, Singapore. csizjb@nus.edu.sg
Research Domain of This Article
Oncology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Clin Oncol. Sep 14, 2018; 9(5): 90-97 Published online Sep 14, 2018. doi: 10.5306/wjco.v9.i5.90
Resistance to FLT3 inhibitors in acute myeloid leukemia: Molecular mechanisms and resensitizing strategies
Jianbiao Zhou, Wee-Joo Chng
Jianbiao Zhou, Wee-Joo Chng, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Singapore
Jianbiao Zhou, Wee-Joo Chng, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
Wee-Joo Chng, Department of Hematology-Oncology, National University Cancer Institute, NUHS, Singapore 119228, Singapore
Author contributions: Zhou J and Chng WJ reviewed the literature and wrote the manuscript.
Supported bythe Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program (to Chng WJ); and NMRC Clinician-Scientist IRG Grant, No. CNIG11nov38 (to Zhou J); Chng WJ is also supported by NMRC Clinician Scientist Investigator award; partially supported by the RNA Biology Center at CSI Singapore, NUS, from funding by the Singapore Ministry of Education’s Tier 3 grants, No. MOE2014-T3-1-006.
Conflict-of-interest statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Jianbiao Zhou, MD, PhD, Senior Scientist, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 28 Medical Drive, Singapore 119074, Singapore. csizjb@nus.edu.sg
Telephone: +65-65161118 Fax: +65-68739664
Received: June 11, 2018 Peer-review started: June 12, 2018 First decision: July 19, 2018 Revised: August 2, 2018 Accepted: August 6, 2018 Article in press: August 7, 2018 Published online: September 14, 2018 Processing time: 95 Days and 5 Hours
Abstract
FMS-like tyrosine kinase 3 (FLT3) is classified as a type III receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia (AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.
Core tip: FMS-like tyrosine kinase 3 (FLT3) mutations including internal tandem duplication (ITD) or point mutation in tyrosine kinase domain are common genetic abnormalities in acute myeloid leukemia (AML), predicting dismal outcome. The Federal Drug Administration granted the use of Midostaurin (Novartis) in newly diagnosed FLT3-ITD positive AML in April 2017. A number of other FLT3 inhibitors are in different phases of clinical trials. However, emerging drug resistance poses a major challenge for clinicians to use FLT3 inhibitors. In this manuscript, we systematically reviewed mechanism of primary resistance and acquired resistance to FLT3 inhibitors. We then propose different strategies to overcome drug resistance and novel treatment options for FLT3-ITD positive AML.
