mTOR inhibition enhances efficacy of dasatinib in ABL-rearranged Ph-like B-ALL
Metrics: PDF 2044 views | HTML 2427 views | ?
Moran Gotesman1,2, Thanh-Trang T. Vo1, Lee-Or Herzog1, Tiffeny Tea1, Sharmila Mallya1, Sarah K. Tasian3, Marina Konopleva4 and David A. Fruman1
1Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
2Hyundai Cancer Institute, CHOC Children’s Hospital, Orange, CA, USA
3Department of Pediatrics, Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
4Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
David A. Fruman, email: [email protected]
Keywords: acute leukemia; animal model; childhood leukemia; leukemia therapy; tyrosine kinases
Received: November 30, 2017 Accepted: December 29, 2017 Published: January 06, 2018
High-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) include Philadelphia chromosome-positive (Ph+) B-ALL driven by the BCR-ABL1 oncogene and a more recently identified subtype known as BCR-ABL-like or Ph-like B-ALL. A hallmark of both Ph+ and Ph-like B-ALL is constitutive activation of tyrosine kinase signaling that is potentially targetable with tyrosine kinase inhibitors (TKIs). B-ALL cells also receive extracellular signals from the microenvironment that can maintain proliferation and survival following treatment with TKIs. Therefore, there is strong rationale for combining TKIs with other therapies targeting signal transduction pathways. Here we show that combinations of the ABL-directed TKI dasatinib with mTOR kinase inhibitors (TOR-KIs) are more effective than TKI alone against patient-derived Ph-like B-ALL cells harboring rearrangements of ABL1 or ABL2. We also report the establishment of a new human Ph-like B-ALL cell line that is stromal cell-independent in vitro and can be used for xenograft experiments in vivo. These findings provide rationale for clinical testing of TKI plus TOR-KIs in children and adults with Ph-like B-ALL and a new experimental tool to test promising therapeutic strategies in this poor prognosis subtype of B-ALL.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.