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Cell Rep. 2013 Nov 27;5(4):1047-59. doi: 10.1016/j.celrep.2013.10.038. Epub 2013 Nov 21.

Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors.

Author information

1
Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
2
Institut Curie, Centre Universitaire, Bat 110, 91405 Orsay, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 3306, Centre Universitaire, Bat 110, 91405 Orsay, France; Institut National de la Sante et al Recherche Medicale, Unite 1005, Centre Universitaire, Bat 110, 91405 Orsay, France.
3
Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, 2052 NSW, Australia.
4
Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
5
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
6
Department of Medicine, Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
7
Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia.
8
Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
9
Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3052 VIC, Australia. Electronic address: ricky.johnstone@petermac.org.

Abstract

To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.

PMID:
24268771
PMCID:
PMC3898474
DOI:
10.1016/j.celrep.2013.10.038
[Indexed for MEDLINE]
Free PMC Article

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