Dataset Information

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

ABSTRACT: Potent FLT3 inhibitors, such as quizartinib (AC220), have shown promise in treating acute myeloid leukemia (AML) containing FLT3 internal tandem duplication (ITD) mutations. However, responses are not durable and resistance develops within months. In this study, we outline a two-step model of resistance whereby extrinsic microenvironmental proteins FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) protect FLT3-ITD+ MOLM14 cells from AC220, providing time for subsequent accumulation of ligand-independent resistance mechanisms. FL directly attenuated AC220 inhibition of FLT3, consistent with previous reports. Conversely, FGF2 promoted resistance through activation of FGFR1 and downstream MAPK effectors; these resistant cells responded synergistically to combinatorial inhibition of FGFR1 and FLT3. Removing FL or FGF2 from ligand-dependent resistant cultures transiently restored sensitivity to AC220, but accelerated acquisition of secondary resistance via reactivation of FLT3 and RAS/MAPK signaling. FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations. Overall, these results support a strategy of early combination therapy to target early survival signals from the bone marrow microenvironment, in particular FGF2, to improve the depth of response in FLT3-ITD AML. Cancer Res; 76(22); 6471-82. ©2016 AACR.

SUBMITTER: Traer E

PROVIDER: S-EPMC5290120 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Traer Elie E Martinez Jacqueline J Javidi-Sharifi Nathalie N Agarwal Anupriya A Dunlap Jennifer J English Isabel I Kovacsovics Tibor T Tyner Jeffrey W JW Wong Melissa M Druker Brian J BJ

Cancer research 20160926 22

Potent FLT3 inhibitors, such as quizartinib (AC220), have shown promise in treating acute myeloid leukemia (AML) containing FLT3 internal tandem duplication (ITD) mutations. However, responses are not durable and resistance develops within months. In this study, we outline a two-step model of resistance whereby extrinsic microenvironmental proteins FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) protect FLT3-ITD+ MOLM14 cells from AC220, providing time for subsequent accumulation of ligan ...[more]

PMID: 27671675

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Project description:Mutations in the fms-like tyrosine kinase 3 (FLT3) gene are detected in approximately one-third of patients with newly diagnosed acute myeloid leukemia (AML). These consist of the more common FLT3-internal tandem duplication (ITD) in approximately 20-25% of AML cases, and point mutations in the tyrosine kinase domain (TKD) in approximately 5-10%. FLT3 mutations, especially FLT3-ITD, are associated with proliferative disease, increased risk of relapse, and inferior overall survival when treated with conventional regimens. However, the recent development of well tolerated and active FLT3 inhibitors has significantly improved the outcomes of this aggressive subtype of AML. The multikinase inhibitor midostaurin was approved by the United States Food and Drug Administration (US FDA) in April 2017 for the frontline treatment of patients with FLT3-mutated (either ITD or TKD) AML in combination with induction chemotherapy, representing the first new drug approval in AML in nearly two decades. In November 2018, the US FDA also approved the second-generation FLT3 inhibitor gilteritinib as a single agent for patients with relapsed or refractory FLT3-mutated AML. Promising phase I and II efficacy data for quizartinib is likely to lead to a third regulatory approval in relapsed/refractory AML in the near future. However, despite the significant progress made in managing FLT3-mutated AML, many questions remain regarding the best approach to integrate these inhibitors into combination regimens, and also the optimal sequencing of different FLT3 inhibitors in various clinical settings. This review comprehensively examines the FLT3 inhibitors currently in clinical development, with an emphasis on their spectra of activity against different FLT3 mutations and other kinases, clinical safety and efficacy data, and their current and future roles in the management of AML. The mechanisms of resistance to FLT3 inhibitors and potential combination strategies to overcome such resistance pathways are also discussed.

Dataset Information

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

Publications

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

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