FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia

Elie Traer, Jacqueline Martinez, Nathalie Javidi-Sharifi, Anupriya Agarwal, Jennifer Dunlap, Isabel English, Tibor Kovacsovics, Jeffrey Tyner, Melissa Wong, Brian Druker

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27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6471-6482
Number of pages12
JournalCancer Research
Volume76
Issue number22
DOIs
StatePublished - Nov 15 2016

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Fibroblast Growth Factor 2
Acute Myeloid Leukemia
Bone Marrow
Ligands
Mutation
Stromal Cells
Secondary Prevention
Recurrence
Survival
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia. / Traer, Elie; Martinez, Jacqueline; Javidi-Sharifi, Nathalie; Agarwal, Anupriya; Dunlap, Jennifer; English, Isabel; Kovacsovics, Tibor; Tyner, Jeffrey; Wong, Melissa; Druker, Brian.

In: Cancer Research, Vol. 76, No. 22, 15.11.2016, p. 6471-6482.

Research output: Contribution to journalArticle

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AU - Martinez, Jacqueline

AU - Javidi-Sharifi, Nathalie

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AU - Dunlap, Jennifer

AU - English, Isabel

AU - Kovacsovics, Tibor

AU - Tyner, Jeffrey

AU - Wong, Melissa

AU - Druker, Brian

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