title: Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia.
abstract: In acute myeloid leukemia (AML), about 25-30% of patients harbor a constitutively active receptor tyrosine kinase (RTK) FLT3 encoded by a FLT3 allele harboring internal tandem duplication (FLT3-ITD) mutation. The presence of FLT3-ITD correlates with poor prognosis in AML and it makes FLT3 an attractive therapeutic target in AML. Unfortunately, to date small-molecule inhibitors of FLT3 have resulted in only partial and transient clinical responses with residual leukemic blasts resistant to FLT3 inhibitors detected in blood or bone marrow. In this study, we investigated whether the RTK Axl is responsible for resistance of FLT3-ITD(+) AML cells to PKC412 and AC220, FLT3 inhibitors currently under clinical trials for FLT3-ITD(+) AML patients. Upon treatment with PKC412 or AC220, phosphorylation of Axl was significantly enhanced in the FLT3-ITD(+) MV4-11 AML cell line and in primary blasts from a FLT3-ITD(+) AML patient. Consistently, a PKC412-resistant AML cell line and PKC412-resistant primary blasts from FLT3-ITD(+) AML patients had significantly higher levels of constitutively phosphorylated Axl and total Axl when compared with a PKC412-sensitive AML cell line and PKC412-sensitive primary blasts from FLT3-ITD(+) AML patients. We also found that resistance of AML cells against the FLT3 inhibitor PKC412 and AC220 was substantially diminished by the inhibition of Axl via a small-molecule inhibitor TP-0903, a soluble receptor Axl fusion protein Axl-Fc or knockdown of Axl gene expression by shRNA. Collectively, our study suggests that Axl is required for resistance of FLT3-ITD(+) AML cells against the FLT3 inhibitor PKC412 and AC220, and that inhibition of Axl activation may overcome resistance to FLT3-targeted therapy in FLT3-ITD(+) AML.
authors.affiliation: Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: I-K
authors.initials: IK
authors.lastname: Park
authors.affiliation: Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mundy-Bosse
authors.affiliation: Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Whitman
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Tolero Pharmaceuticals, Inc., Lehi, UT, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Warner
authors.affiliation: Tolero Pharmaceuticals, Inc., Lehi, UT, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Bearss
authors.affiliation: Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.|Division of Hematology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Blum
authors.affiliation: Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.|Division of Hematology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Comprehensive Cancer Center and The James Cancer Hospital, The Ohio State University, Columbus, OH, USA.|Division of Hematology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human