Journal article

Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors

Michaela Waibel, Vanessa S Solomon, Deborah A Knight, Rachael A Ralli, Sang-Kyu Kim, Kellie-Marie Banks, Eva Vidacs, Clemence Virely, Keith CS Sia, Lauryn S Bracken, Racquel Collins-Underwood, Christina Drenberg, Laura B Ramsey, Sara C Meyer, Megumi Takiguchi, Ross A Dickins, Ross Levine, Jacques Ghysdael, Mark A Dawson, Richard B Lock Show all

CELL REPORTS | CELL PRESS | Published : 2013


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 inhibi..

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Funding Acknowledgements

R.W.J. is a Principal Research Fellow of the National Health and Medical Research Council of Australia (NHMRC) and is supported by NHMRC Program and Project Grants, Susan G. Komen Breast Cancer Foundation, Prostate Cancer Foundation of Australia, Cancer Council Victoria, Leukemia Foundation of Australia, Victorian Breast Cancer Research Consortium, Victorian Cancer Agency, and Australian Rotary Health Foundation. M. W. was supported by a fellowship from the Deutsche Forschungsgemeinschaft and funding from the NHMRC. V. S. S. received funding from the NHMRC, the Peter MacCallum Cancer Foundation, and Bioplatforms Australia. S. C. M. received funding from the Swiss National Science Foundation and the Huggenberger-Bischoff Foundation for Cancer Research. R. A. D. is a Sylvia and Charles Viertel Foundation Senior Medical Research Fellow. R. B. L. is a Senior Research Fellow of the NHMRC. C. G. M. is supported by ALSAC of St. Jude Children's Research Hospital and the Pew Charitable Trusts. Work in J.G.'s laboratory was supported by funds from Institute Curie, CNRS, INSERM, INCA, and Ligue Contre le Cancer (Equipe labellisee Ligue). M. A. D. is a Wellcome-Beit Intermediate Clinical Fellow. We thank Drs. J. Shortt, M. Bishton, E. Hawkins, K. Hannan, K. Kinross, A. Alsop, and D. Ritchie for valuable discussions and reagents, K. Stanley for technical assistance, and the Tissue Resources Laboratory of St. Jude Children's Research Hospital for patient samples. We thank Novartis, Sanofi-Aventis, and Abbott for supply of reagents. Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and the Sydney Children's Hospitals Network. JAK2 mutant xenografts were established in collaboration with the Children's Oncology Group.