Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2013-11, Vol.5 (4), p.1047-1059

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •Bcl-2 and Bcl-xL are the key survival factors downstream of oncogenic JAK2•Combined targeting of JAK2 and Bcl-2/Bcl-xL is highly efficacious in vivo•Combination therapy is well tolerated in preclinical models of JAK2-driven ALL•Combination therapy can overcome and circumvent resistance to JAK2 inhibitors Better therapeutic options are required for mutant JAK2-driven hemopoietic malignancies to overcome intrinsic and acquired therapy resistance. Johnstone and colleagues functionally dissect signaling pathways downstream of hyperactive JAK2 and define the STAT5-Bcl-2/Bcl-xL axis as crucial for tumor cell survival and development of acquired JAK inhibitor resistance. Combined inhibition of this oncogenic JAK2 signaling network at two critical points—JAK2 and Bcl-2/Bcl-xL—proved highly efficacious in vivo and was able to circumvent and overcome acquired resistance to single-agent JAK inhibitors.