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

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• 作者：Michaela Waibel ; Vanessa聽S. Solomon ; Deborah聽A. Knight ; Rachael聽A. Ralli ; Sang-Kyu Kim ; Kellie-Marie Banks ; Eva Vidacs ; Clemence Virely ; Keith聽C.S. Sia ; Lauryn聽S. Bracken ; Racquel Collins-Underwood ; Christina Drenberg ; Laura聽B. Ramsey ; Sara聽C. Meyer ; Megumi Takiguchi ; Ross聽A. Dickins ; Ross Levine ; Jacques Ghysdael ; Mark聽A. Dawson ; Richard聽B. Lock ; et al.
• 刊名：Cell Reports
• 出版年：27 November, 2013
• 年：2013
• 卷：5
• 期：4
• 页码：1047-1059
• 全文大小：2551 K

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Summary

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聽were constitutively active, and gene expression聽profiling of TEL-JAK2 T-ALL cells revealed the聽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聽mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able聽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聽and provides a clearly superior therapeutic benefit聽than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.