Abstract 1885: Selective Polo-like Kinase 1 (PLK1) inhibitor PCM-075 is highly active alone and shows synergy when combined with FLT3 inhibitors in models of acute myeloid leukemia (AML)

2018 ◽  
Author(s):  
Karena Kosco ◽  
Maya Ridinger ◽  
Penn Whitley ◽  
Peter Croucher ◽  
Jeffrey N. Miner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Highly Active ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

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

2016 ◽  
Vol 113 (43) ◽  
pp. E6669-E6678 ◽  
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.

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

Haematologica ◽  
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.

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

Blood ◽  
2014 ◽  
Vol 123 (5) ◽  
pp. 734-742 ◽  
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.

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

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2493
Author(s):  
Sebastian Scholl ◽  
Maximilian Fleischmann ◽  
Ulf Schnetzke ◽  
Florian H. Heidel
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Continuous Treatment ◽  
Next Generation ◽  
Secondary Resistance ◽  
Development Of Resistance ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

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.

FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions

Leukemia ◽  
2020 ◽  
Vol 34 (3) ◽  
pp. 682-696 ◽  
Author(s):  
Ahmad I. Antar ◽  
Zaher K. Otrock ◽  
Elias Jabbour ◽  
Mohamad Mohty ◽  
Ali Bazarbachi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Gelatin-coated Gold Nanoparticles as Carriers of FLT3 Inhibitors for Acute Myeloid Leukemia Treatment

2016 ◽  
Vol 87 (6) ◽  
pp. 927-935 ◽  
Author(s):  
Sorina Suarasan ◽  
Timea Simon ◽  
Sanda Boca ◽  
Ciprian Tomuleasa ◽  
Simion Astilean
Keyword(s):  
Gold Nanoparticles ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Flt3 Inhibitors ◽  
Leukemia Treatment ◽  
Acute Myeloid

Recent advances in FLT3 inhibitors for acute myeloid leukemia

2020 ◽  
Vol 12 (10) ◽  
pp. 961-981 ◽  
Author(s):  
Lexian Tong ◽  
Xuemei Li ◽  
Yongzhou Hu ◽  
Tao Liu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Clinical Stage ◽  
Wild Type ◽  
New Techniques ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Target Activity ◽  
Acute Myeloid

Fms-like tyrosine kinase-3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) cases, suggesting FLT3 as an attractive target for AML treatment. Early FLT3 inhibitors enhance antileukemia efficacy by inhibiting multiple targets, and thus had stronger off-target activity, increasing their toxicity. Recently, a number of potent and selective FLT3 inhibitors have been developed, many of which are effective against multiple mutations. This review outlines the evolution of AML-targeting FLT3 inhibitors by focusing on their chemotypes, selectivity and activity over FLT3 wild-type and FLT3 mutations as well as new techniques related to FLT3. Compounds that currently enter the late clinical stage or have entered the market are also briefly reported.

Sign in / Sign up

Export Citation Format

Share Document