| Autor: |
van Oosterwijk JG; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Buelow DR; Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Drenberg CD; Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Vasilyeva A; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Li L; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Shi L; Department of Biostatistics., Wang YD; Department of Computational Biology., Finkelstein D; Department of Computational Biology., Shurtleff SA; Department of Pathology, and., Janke LJ; Department of Pathology, and., Pounds S; Department of Biostatistics., Rubnitz JE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Inaba H; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Pabla N; Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Baker SD; Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. |
| Abstrakt: |
Oncogenic addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that harbors the FLT3-internal tandem duplication (FLT3-ITD) mutation. While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, we used RNA-Seq-based analysis of patient leukemic cells and found that upregulation of the Tec family kinase BMX occurs during sorafenib resistance. This upregulation was recapitulated in an in vivo murine FLT3-ITD-positive (FLT3-ITD+) model of sorafenib resistance. Mechanistically, the antiangiogenic effects of sorafenib led to increased bone marrow hypoxia, which contributed to HIF-dependent BMX upregulation. In in vitro experiments, hypoxia-dependent BMX upregulation was observed in both AML and non-AML cell lines. Functional studies in human FLT3-ITD+ cell lines showed that BMX is part of a compensatory signaling mechanism that promotes AML cell survival during FLT3 inhibition. Taken together, our results demonstrate that hypoxia-dependent upregulation of BMX contributes to therapeutic resistance through a compensatory prosurvival signaling mechanism. These results also reveal the role of off-target drug effects on tumor microenvironment and development of acquired drug resistance. We propose that the bone marrow niche can be altered by anticancer therapeutics, resulting in drug resistance through cell-nonautonomous microenvironment-dependent effects. |
