Resistance to FLT3 inhibitors in acute myeloid leukemia: Molecular mechanisms and resensitizing strategies

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.

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ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1603876113 ◽

2016 ◽

Vol 113 (43) ◽

pp. E6669-E6678 ◽

Cited By ~ 35

Author(s):

Mark A. Gregory ◽

Angelo D’Alessandro ◽

Francesca Alvarez-Calderon ◽

Jihye Kim ◽

Travis Nemkov ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mitochondrial Oxidative Stress ◽

Flt3 Inhibitor ◽

A Genome ◽

Flt3 Inhibitors ◽

Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

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FLT3 inhibitors in acute myeloid leukemia

Journal of Hematology & Oncology ◽

10.1186/s13045-018-0675-4 ◽

2018 ◽

Vol 11 (1) ◽

Cited By ~ 40

Author(s):

Mei Wu ◽

Chuntuan Li ◽

Xiongpeng Zhu

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Flt3 Inhibitors ◽

Acute Myeloid

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WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia

Cell Death and Disease ◽

10.1038/s41419-021-04467-0 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Yunqi Zhu ◽

Xiangmin Tong ◽

Ying Wang ◽

Xiaoya Lu

Keyword(s):

Acute Myeloid Leukemia ◽

Tumor Suppressor ◽

Transcriptional Activation ◽

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Hematologic Malignancy ◽

Apoptotic Pathway ◽

Acute Myeloid

AbstractAcute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

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Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia

Haematologica ◽

10.3324/haematol.2020.257964 ◽

2020 ◽

Author(s):

Alisa Damnernsawad ◽

Daniel Bottomly ◽

Stephen E. Kurtz ◽

Christopher A. Eide ◽

Shannon K. McWeeney ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Ex Vivo ◽

Mek Inhibitors ◽

Genome Wide ◽

A Genome ◽

Flt3 Mutations ◽

Flt3 Inhibitors ◽

Crispr Screen ◽

Acute Myeloid

Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly, MAPK and/or MTOR complex1 (MTORC1) activity were upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, or sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.

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MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells

Blood ◽

10.1182/blood-2013-04-493858 ◽

2014 ◽

Vol 123 (5) ◽

pp. 734-742 ◽

Cited By ~ 13

Author(s):

Suiyang Liu ◽

Li Yin ◽

Dina Stroopinsky ◽

Hasan Rajabi ◽

Alexandre Puissant ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Receptor Activation ◽

Leukemia Cells ◽

Receptor Targeting ◽

Potential Approach ◽

Key Points ◽

Flt3 Inhibitors ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

Key Points The MUC1-C oncoprotein is aberrantly expressed in AML cells and contributes to activation of the mutant FLT3 receptor. Targeting MUC1-C thus inhibits FLT3 signaling and represents a potential approach for AML cells resistant to FLT3 inhibitors.

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