FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia.
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.
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. traere@ohsu.edu.|Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
Elie
E
Traer
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Jacqueline
J
Martinez
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Nathalie
N
Javidi-Sharifi
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.|Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.
Anupriya
A
Agarwal
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.|Department of Anatomic Pathology, Oregon Health and Science University, Portland, Oregon.
Jennifer
J
Dunlap
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Isabel
I
English
BMT, Blood and Marrow Transplant, Huntsman Cancer Institute, Salt Lake City, Utah.
Tibor
T
Kovacsovics
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.|Department of Cell, Developmental, and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
Jeffrey W
JW
Tyner
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.|Department of Cell, Developmental, and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
Melissa
M
Wong
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.|Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.|Howard Hughes Medical Institute, Chevy Chase, Maryland.
Brian J
BJ
Druker
D045744:Cell Line, Tumor; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D059016:Tumor Microenvironment; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
D016222:Fibroblast Growth Factor 2; D051941:fms-Like Tyrosine Kinase 3
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