DLBCL

AACR 2017 poster 2161/12 – Pharmacological downregulation of BFL-1 by CPI203 overcomes ABT-199 resistance in Double Hit Lymphoma

On Monday 3rd April during this year’s American Association for Cancer Research (AACR) annual meeting, a poster (2161 / 12) by Anna Esteve-Arenys, from IDIBAPS, Barcelona, Spain, et al. titled “Pharmacological downregulation of BFL-1 by the BET bromodomain inhibitor CPI203 overcomes ABT-199 resistance in MYC+/BCL2+ double hit lymphoma” was presented.

The group aimed to: assess the anti-tumor effect of ABT-199 (venetoclax) in Double Hit Lymphoma (DHL) cell lines, explore the role of bromodomain inhibition in overcoming resistance to ABT-199, and to evaluate the combination of ABT-199 and CPI203 (BET inhibitor) in in vitro and in vivo models of DHL.

Key Highlights:
  • ABT-199, in a dose and time-dependent manner, decreased cell proliferation
  • A significant decrease in ABT-199 efficacy was reported at 96h in DHL cell lines (cell viability increased from 53–78% from 24 to 96hrs after 100nM treatment)
  • Prolonged exposure of ABT-199 induced BFL-1 overexpression in DHL cell lines
  • BFL-1 upregulation was associated with resistance to ABT-199 in DHL cell lines
  • CPI203 decreased BFL-1 and increased BIM expression in DHL cell lines and primary samples
  • ABT-199 combined with CPI203 demonstrated synergistic pro-apoptotic activity
  • In SCID mice subcutaneously injected with Oci-Ly8 cells, those treated with ABT-199 and CPI203 displayed a significantly larger reduction in tumor growth and size versus those in the control group (P < 0.001)

The poster was concluded by stating that expression and persistence of BFL-1 governs the sensitivity of DHL cells and xenograft models to ABT-199. The group found that BF-L1 expression can be reduced in vitro and in vivo by CPI203 allowing apoptosis to be induced by ABT-199. The group stress that this novel combination should be evaluated clinically in patients with aggressive DHL.

Reference:
  1. Esteve-Arenys A. et al. Pharmacological downregulation of BFL-1 by the BET bromodomain inhibitor CPI203 overcomes ABT-199 resistance in MYC+/BCL2+ double hit lymphoma [Poster]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; 2017. Poster nr [2161 / 12].