Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors

• Published in: Leukemia Vol. 26; no. 10; pp. 2233 - 2244
• Main Authors: Weisberg, E, Liu, Q, Nelson, Erik, Kung, A L, Christie, A L, Bronson, R, Sattler, M, Sanda, T, Zhao, Z, Hur, W, Mitsiades, C, Smith, R, Daley, J F, Stone, R, Galinsky, I, Griffin, J D, Gray, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2012; Nature Publishing Group
• Subjects: 631/67/1059/2326; 631/67/327; 692/699/67/1990/283/1897; 692/700/565/1436/1437; Acute myeloid leukemia; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Bone marrow; Cancer; Cancer Research; Cell survival; Chemoresistance; Clinical trials; Combination therapy; Critical Care Medicine; Dasatinib; Drug resistance; Drug Resistance, Neoplasm; Drug therapy, Combination; Enzyme inhibitors; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; Gene mutations; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Inhibitors; Intensive; Internal Medicine; Janus kinase; Janus Kinases - antagonists & inhibitors; Kinases; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Microenvironments; Mimicry; Mutants; Mutation; Oncology; original-article; Physiological aspects; Progenitor cells; Protein Kinase Inhibitors - administration & dosage; Protein-tyrosine kinase receptors; Proteins; Pyrimidines - administration & dosage; Signal transduction; STAT5 Transcription Factor - metabolism; Staurosporine - administration & dosage; Staurosporine - analogs & derivatives; Stem cells; Stromal Cells - physiology; Synergism; Thiazoles - administration & dosage; Tyrosine; United States > US; stromal-mediated chemoresistance; multi-targeted kinase inhibitor; synergy; acute myeloid leukemia; AC220; PKC412; Antineoplastic agent; Acute myelogenous leukemia; Targeting; Drug interaction; Protooncogene; Jak protein tyrosine kinase; Dasatinib; Treatment resistance; Hematology; Tyrosine kinase inhibitor; FLT3 gene; Stroma; Malignant hemopathy; trk receptor; C-Onc gene; Combined treatment; Multikinase inhibitor; Mutation; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.96

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.