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Combined inhibition of Bcl-2 and NFκB synergistically induces cell death and limits xenograft mouse tumor growth in CTCL

Tabea C. Froehlich, Karin Müller-Decker, Jana D. Braun, Thomas Albrecht, Anne Schroeder, Karsten Gülow, Sergij Goerdt, Peter H. Krammer and Jan P. Nicolay

Key Points

  • ABT-199 and DMF synergistically and specifically induce cell death in CTCL cells via cooperative inhibition of Bcl-2 and NFκB.

  • In vitro and in vivo data suggest this combination as a promising, effective and non-toxic novel therapeutic approach in CTCL treatment.

Abstract

Therapeutic options for cutaneous T cell lymphoma (CTCL) are limited and curative treatment regimens are not available. Thus, new targeted and well-tolerated therapeutic approaches are urgently needed. In this respect, we have recently shown that dimethyl fumerate (DMF) inhibits NFκB acting as a survival factor in CTCL. Similarly, inhibition of the anti-apoptotic protein Bcl-2 has been shown to induce cell death in CTCL especially when combined with HDAC inhibitors. Therefore, we hypothesized that inhibition of Bcl-2 should potentiate NFκB inhibition in a novel combination treatment of CTCL. We show that in vitro the Bcl-2 inhibitors ABT-199 and ABT-263 induced specific cell death in primary CD4+ cells from CTCL patients as well as in the CTCL cell line SeAx, but not in T cells of healthy donors nor in the CTCL cell line HH that lacks Bcl-2. Combined treatment with ABT-199 and DMF caused synergistic cell death specifically in CTCL cells engaging two independent signaling pathways. To verify these findings in vivo, we performed combined ABT-199 and DMF treatment in a xenograft mouse model for CTCL. The combined treatment effectively reduced tumor growth and increased overall survival via synergistic induction of CTCL cell death and suppression of tumor cell proliferation. Essentially, the combination treatment was superior to ABT-199 monotherapy with respect to both efficacy and tolerability. To sum up, our data provide proof of principle for the therapeutic potential of combining Bcl-2 and NFκB inhibitors in treating CTCL. Next, this potential should be explored further in a clinical study.

  • Submitted January 28, 2019.
  • Revision received June 2, 2019.
  • Accepted May 31, 2019.