title: Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors.
abstract: Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase Fms-like tyrosine kinase-3 (FLT3). Protein tyrosine kinases are integral components of signaling cascades that have a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors. We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Weisberg
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: Erik
authors.initials: E
authors.lastname: Nelson
authors.forename: A L
authors.initials: AL
authors.lastname: Kung
authors.forename: A L
authors.initials: AL
authors.lastname: Christie
authors.forename: R
authors.initials: R
authors.lastname: Bronson
authors.forename: M
authors.initials: M
authors.lastname: Sattler
authors.forename: T
authors.initials: T
authors.lastname: Sanda
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: W
authors.initials: W
authors.lastname: Hur
authors.forename: C
authors.initials: C
authors.lastname: Mitsiades
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.forename: J F
authors.initials: JF
authors.lastname: Daley
authors.forename: R
authors.initials: R
authors.lastname: Stone
authors.forename: I
authors.initials: I
authors.lastname: Galinsky
authors.forename: J D
authors.initials: JD
authors.lastname: Griffin
authors.forename: N
authors.initials: N
authors.lastname: Gray
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage; D050799:STAT5 Transcription Factor / Q000378:metabolism; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives; D017154:Stromal Cells / Q000502:physiology; D013844:Thiazoles / Q000008:administration & dosage; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013844:Thiazoles; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D053612:Janus Kinases; D019311:Staurosporine; C059539:midostaurin; D000069439:Dasatinib