scholarly journals Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 245
Author(s):  
Motoki Eguchi ◽  
Yosuke Minami ◽  
Ayumi Kuzume ◽  
SungGi Chi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Active Form ◽  
Novel Agents ◽  
Type I ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

FLT3-ITD and FLT3-TKD mutations were observed in approximately 20 and 10% of acute myeloid leukemia (AML) cases, respectively. FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib show excellent response rates in patients with FLT3-mutated AML, but its duration of response may not be sufficient yet. The majority of cases gain secondary resistance either by on-target and off-target abnormalities. On-target mutations (i.e., FLT3-TKD) such as D835Y keep the TK domain in its active form, abrogating pharmacodynamics of type II FLT3 inhibitors (e.g., midostaurin and quizartinib). Second generation type I inhibitors such as gilteritinib are consistently active against FLT3-TKD as well as FLT3-ITD. However, a “gatekeeper” mutation F691L shows universal resistance to all currently available FLT3 inhibitors. Off-target abnormalities are consisted with a variety of somatic mutations such as NRAS, AXL and PIM1 that bypass or reinforce FLT3 signaling. Off-target mutations can occur just in the primary FLT3-mutated clone or be gained by the evolution of other clones. A small number of cases show primary resistance by an FL-dependent, FGF2-dependent, and stromal CYP3A4-mediated manner. To overcome these mechanisms, the development of novel agents such as covalently-coupling FLT3 inhibitor FF-10101 and the investigation of combination therapy with different class agents are now ongoing. Along with novel agents, gene sequencing may improve clinical approaches by detecting additional targetable mutations and determining individual patterns of clonal evolution.

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.

Mechanisms of Resistance to Targeted Therapies in Acute Myeloid Leukemia and Chronic Myeloid Leukemia

2012 ◽  
pp. 685-689
Author(s):  
Catherine C. Smith ◽  
Neil P. Shah
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Targeted Therapies ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Oncogenic Signaling ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Clinical Resistance ◽  
Acute Myeloid

Overview: Small molecule kinase inhibitors of BCR-ABL in chronic myeloid leukemia (CML) and of FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in acute myeloid leukemia (AML) have been successful at achieving remissions in these diseases as monotherapy, but these leukemias do not initially respond in a subset of patients (primary resistance) and they progress in an additional group of patients after an initial response (secondary resistance). Resistance to these agents can be divided into mechanisms that allow reactivation kinase activity and those that bypass reliance on oncogenic signaling mediated by the target kinase. Elucidation of clinical resistance mechanisms to targeted therapies for patients can provide important insights into disease pathogenesis and signaling.

scholarly journals Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3-inhibitors

2020 ◽  
pp. bloodcandisc.0143.2020
Author(s):  
Ahmad S. Alotaibi ◽  
Musa Yilmaz ◽  
Rashmi Kanagal-Shamanna ◽  
Sanam Loghavi ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Type I ◽  
Type Ii ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

scholarly journals FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020 ◽  
Vol 10 ◽  
Author(s):  
Vanessa E. Kennedy ◽  
Catherine C. Smith
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Clonal Evolution ◽  
The United States ◽  
Extracellular Signaling ◽  
Flt3 Inhibitors ◽  
Novel Therapeutic Strategies ◽  
Acute Myeloid

The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

Acquired BCR-ABL1 fusion and IDH1 clonal evolution following BCL2 inhibitor treatment in refractory acute myeloid leukemia

2021 ◽  
Vol 100 ◽  
pp. 106494
Author(s):  
Diego Adrianzen-Herrera ◽  
Ximena Jordan-Bruno ◽  
Katherine A. Devitt ◽  
Joanna L. Conant ◽  
Juli-Anne Gardner
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Refractory Acute Myeloid Leukemia ◽  
Inhibitor Treatment ◽  
Acute Myeloid

scholarly journals Novel agents in acute myeloid leukemia

2012 ◽  
Vol 96 (2) ◽  
pp. 178-185 ◽  
Author(s):  
Alexander Ungewickell ◽  
Bruno C. Medeiros
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Novel Agents ◽  
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.

Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Makowka ◽  
Verena Stolp ◽  
Karoline Stoschek ◽  
Hubert Serve
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Therapy Response ◽  
Secondary Resistance ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Slow Progress ◽  
Molecular Aberrations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

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