TY - JOUR
T1 - FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia
AU - Traer, Elie
AU - Martinez, Jacqueline
AU - Javidi-Sharifi, Nathalie
AU - Agarwal, Anupriya
AU - Dunlap, Jennifer
AU - English, Isabel
AU - Kovacsovics, Tibor
AU - Tyner, Jeffrey W.
AU - Wong, Melissa
AU - Druker, Brian J.
N1 - Funding Information:
We thank C. Tognon and members of the Druker lab for helpful discussions, and A. Agarwal for the cytokine plate. We would also like to thank David K. Edwards V for his help in identifying FLT3 mutations. E. Traer was supported by the Oregon Clinical and Translational Research Institute grant number KL2TR000152from the National Center for Advancing Translational Sciencesat the NIH. B.J. Druker is supported by the Howard Hughes Medical Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-3569
DO - 10.1158/0008-5472.CAN-15-3569
M3 - Article
C2 - 27671675
AN - SCOPUS:84995477307
SN - 0008-5472
VL - 76
SP - 6471
EP - 6482
JO - Cancer Research
JF - Cancer Research
IS - 22
ER -