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Review
. 2020 Nov 17;9(11):2493.
doi: 10.3390/cells9112493.

Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments

Sebastian Scholl  1 , Maximilian Fleischmann  1 , Ulf Schnetzke  1 , Florian H Heidel  2
Affiliations
Review

Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments

Sebastian Scholl et al. Cells. .

Abstract

Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML.

Keywords: AML; FLT3; FLT3-ITD; FLT3-TKD; FMS-like tyrosine kinase 3; acute myeloid leukemia; crenolanib; gilteritinib; midostaurin; quizartinib; resistance.

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Conflict of interest statement

S.S.: Consultancy, Research Funding (Pfizer, Novartis); F.H.H.: Consultancy, Research Funding (Novartis, Pfizer, Celgene/BMS)

Figures

Figure 1
Figure 1
A graphical overview of in vitro sensitivity versus the resistance of FLT3 inhibitors (green—sensitive; orange—intermediate; red—resistant) towards distinct subtypes of activating FLT3 mutations, including compound mutations of FLT3 (ITD plus TKD) [61,62,63,64,65,66,67,68,69].
Figure 2
Figure 2
Potential signaling pathways to overcome resistance to FLT3 inhibitors.
See this image and copyright information in PMC

References

    1. Nakao M., Yokota S., Iwai T., Kaneko H., Horiike S., Kashima K., Sonoda Y., Fujimoto T., Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918. - PubMed
    1. Yokota S., Kiyoi H., Nakao M., Iwai T., Misawa S., Okuda T., Sonoda Y., Abe T., Kahsima K., Matsuo Y., et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia. 1997;11:1605–1609. doi: 10.1038/sj.leu.2400812. - DOI - PubMed
    1. Döhner H., Estey E., Grimwade D., Amadori S., Appelbaum F.R., Büchner T., Dombret H., Ebert B.L., Fenaux P., Larson R.A., et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–447. doi: 10.1182/blood-2016-08-733196. - DOI - PMC - PubMed
    1. O’Donnell M.R., Tallman M.S., Abboud C.N., Altman J.K., Appelbaum F.R., Arber D.A., Bhatt V., Bixby D., Blum W., Coutre S.E., et al. Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 2017;15:926–957. doi: 10.6004/jnccn.2017.0116. - DOI - PubMed
    1. Papaemmanuil E., Gerstung M., Bullinger L., Gaidzik V.I., Paschka P., Roberts N.D., Potter N.E., Heuser M., Thol F., Bolli N., et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N. Engl. J. Med. 2016;374:2209–2221. doi: 10.1056/NEJMoa1516192. - DOI - PMC - PubMed

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