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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics
  • Bcl-2-Like Protein 11
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Cell Survival
  • Drug Resistance, Neoplasm*
  • Gene Expression Profiling
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Nitrophenols / pharmacology
  • Piperazines / pharmacology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Proto-Oncogene Proteins / genetics
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • Transplantation, Heterologous
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / genetics

Substances

  • ABT-737
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l1 protein, mouse
  • Bcl2l11 protein, mouse
  • Biphenyl Compounds
  • INCB018424
  • Membrane Proteins
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Pyrimidines
  • Sulfonamides
  • TG101209
  • bcl-X Protein
  • Jak2 protein, mouse
  • Janus Kinase 2

Associated data

  • GEO/GSE51250