FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

Traer, Elie; Martinez, Jacqueline; Javidi-Sharifi, Nathalie; Agarwal, Anupriya; English, Isabel; Kovacsovics, Tibor; Tyner, Jeffrey W.; Wong, Melissa H.; Druker, Brian J.

doi:10.1158/0008-5472.can-15-3569

Cited by 123 publications

(152 citation statements)

References 48 publications

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“…It would be interesting to test whether treating patients who are clinically resistant to AC220 with FGF inhibitor or MAPK inhibitor would re-sensitize leukemic cells to AC220. Of note, our conclusion is also further supported by a recent report showing that FGF2 promoted resistance to AC220 through activation of FGFR1 and downstream MAPK effectors in AML cells (54). In summary, our study identified and delineated novel functional roles for SPRY3 and GSK3 genes whose deletions lead to FLT3 inhibitor resistance and provided new insights into the downstream signaling pathways regulated by FLT3 (Fig.…”

Section: Discussionsupporting

confidence: 88%

A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220

Hou

Wang

et al. 2017

Cancer Research

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Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. The mechanisms underlying drug resistance in AML are poorly understood. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most common molecular abnormality in AML. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3-ITD-positive and -negative AML patients and as maintenance therapy. To understand the mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR pooled library to screen new genes whose loss of function confers resistance to AC220. We identified SPRY3, an intracellular inhibitor of FGF signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated that re-activation of downstream FGF/Ras/ERK and Wnt signaling as major mechanisms of resistance to AC220. We confirmed these findings in primary AML patient samples. Expression of SPRY3 and GSK3A was dramatically reduced in AC220-resistant AML samples, and SPRY3-deleted primary AML cells were resistant to AC220. Intriguingly, expression of SPRY3 was greatly reduced in GSK3 knockout AML cells, which positioned SPRY3 downstream of GSK3 in the resistance pathway. Taken together, our study identified novel genes whose loss of function conferred resistance to a selective FLT3 inhibitor, providing new insight into signaling pathways that contribute to acquired resistance in AML.

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Section: Discussionsupporting

confidence: 88%

A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220

Hou

Wang

et al. 2017

Cancer Research

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“…Increased FLT3L secretion by the bone marrow microenvironment after chemotherapy stimulates AML cells with FLT3 mutations, which remain responsive to FLT3L despite constitutive FLT3 activation, and decreases sensitivity to FLT3 inhibitors [27,28]. Similarly, increased fibroblast growth factor 2 (FGF2) secretion by the bone marrow microenvironment after chemotherapy or FLT3 inhibitor therapy stimulates AML cells with FLT3 mutations via binding to fibroblast growth factor receptor (FGFR) 1 on AML cells [53]. Bone marrow stroma-mediated resistance also results from enhanced CXCL12-CXCR4-mediated homing [54], at least in part due to Pim-1 overexpression, as Pim-1 phosphorylates CXCR4, enabling its cell surface translocation and expression [55].…”

Section: Flt3 Inhibitor Resistancementioning

confidence: 99%

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Larrosa-García

Baer

2017

Molecular Cancer Therapeutics

247

209

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The receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy produces clinical responses, they are usually incomplete and transient, and resistance develops rapidly. Diverse combination therapies have been suggested to potentiate the efficacy of FLT3 inhibitors and to prevent development of resistance or overcome resistance. Combinations with epigenetic therapies, proteasome inhibitors, downstream kinase inhibitors, phosphatase activators and other drugs that alter signaling are being explored. This review summarizes the current status of translational and clinical research on FLT3 inhibitors in AML, and discusses novel combination approaches.

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“…Many studies, [46][47][48][49][50][51] including our own, [52][53][54] have shown that the bone marrow microenvironment contributes significantly to the development of drug resistance in the setting of AML. Leukemia cells circulating in the peripheral blood are rapidly cleared by FLT3 inhibitors while leukemia cells within the microenvironment respond more slowly and a small number of leukemia cells persist despite treatment.…”

Section: Extrinsic Resistance Mechanismsmentioning

confidence: 98%

<p>Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date</p>

Fletcher¹,

Joshi²,

Traer³

2020

CMAR

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Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by rapid, uncontrolled cell growth of immature myeloid cells (blasts). There are numerous genetic abnormalities in AML, many of which are prognostic, but an increasing number are targets for drug therapy. One of the most common genetic abnormalities in AML are activating mutations in the FMS-like tyrosine kinase 3 receptor (FLT3). As a receptor tyrosine kinase, FLT3 was the first targetable genetic abnormality in AML. The first generation of FLT3 inhibitors were broad-spectrum kinase inhibitors that inhibited FLT3 among other proteins. Although clinically active, first-generation FLT3 inhibitors had limited success as single agents. This led to the development of a second generation of more selective FLT3 inhibitors. This review focuses on quizartinib, a potent second-generation FLT3 inhibitor. We discuss the clinical trial development, mechanisms of resistance, and the recent FDA decision to deny approval for quizartinib as a single agent in relapsed/refractory AML.

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FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

Cited by 123 publications

References 48 publications

A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220

A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

<p>Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date</p>

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